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New roles for mitochondrial proteases in health, ageing and disease

Key Points

  • The human mitochondrial degradome (also referred to as the mitodegradome) is defined as the complete set of proteases and their homologues that function in mitochondria from human cells and tissues.

  • Mitochondrial proteases (mitoproteases) can be divided into three subgroups, depending on their function and location: intrinsic mitoproteases, the functional activity of which is mostly performed in the mitochondrion; pseudo-mitoproteases, which are catalytically deficient but functionally proficient mitochondrial proteins; and transient or roaming mitoproteases, which are translocated to mitochondria only under certain circumstances to exert additional proteolytic activities.

  • Mitoproteases are highly specific and modulate many biochemical activities that are essential for mitochondrial function and integrity, such as trafficking, processing and activation of mitochondrial proteins, mitochondrial dynamics, mitophagy and apoptosis.

  • Mitoproteases greatly affect the control of ageing and longevity; changes in the expression and activity of several mitoproteases have been linked to alterations in healthspan and lifespan and to the regulation of stress responses that promote longevity.

  • Impaired or dysregulated function of mitoproteases is associated with various pathological conditions, including cancer, metabolic syndromes and neurodegenerative disorders. In addition, at least 12 human hereditary diseases are caused by mutations in genes encoding mitoproteases and pseudo-mitoproteases.

Abstract

Recent advances in mitochondrial biology have revealed the high diversity and complexity of proteolytic enzymes that regulate mitochondrial function. We have classified mitochondrial proteases, or mitoproteases, on the basis of their function and location, and defined the human mitochondrial degradome as the complete set of mitoproteases that are encoded by the human genome. In addition to their nonspecific degradative functions, mitoproteases perform highly regulated proteolytic reactions that are important in mitochondrial function, integrity and homeostasis. These include protein synthesis, quality control, mitochondrial biogenesis and dynamics, mitophagy and apoptosis. Impaired or dysregulated function of mitoproteases is associated with ageing and with many pathological conditions such as neurodegenerative disorders, metabolic syndromes and cancer. A better understanding of the mitochondrial proteolytic landscape and its modulation may contribute to improving human lifespan and 'healthspan'.

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Figure 1: Classification of human mitoproteases.
Figure 2: Functions of mitochondrial processing peptidases.
Figure 3: Regulation of mitochondrial quality control.
Figure 4: Proteolytic regulation of mitochondrial functions.

References

  1. Turk, B., Turk, D. & Turk, V. Protease signalling: the cutting edge. EMBO J. 31, 1630–1643 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. López-Otín, C. & Bond, J. S. Proteases: multifunctional enzymes in life and disease. J. Biol. Chem. 283, 30433–30437 (2008).

    PubMed  PubMed Central  Google Scholar 

  3. López-Otín, C. & Hunter, T. The regulatory crosstalk between kinases and proteases in cancer. Nature Rev. Cancer 10, 278–292 (2010).

    Google Scholar 

  4. Koppen, M. & Langer, T. Protein degradation within mitochondria: versatile activities of AAA proteases and other peptidases. Crit. Rev. Biochem. Mol. Biol. 42, 221–242 (2007).

    CAS  PubMed  Google Scholar 

  5. Anand, R., Langer, T. & Baker, M. J. Proteolytic control of mitochondrial function and morphogenesis. Biochim. Biophys. Acta 1833, 195–204 (2013).

    CAS  PubMed  Google Scholar 

  6. Rugarli, E. I. & Langer, T. Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 31, 1336–1349 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Goard, C. A. & Schimmer, A. D. Mitochondrial matrix proteases as novel therapeutic targets in malignancy. Oncogene 33, 2690–2699 (2014).

    CAS  PubMed  Google Scholar 

  8. Bulteau, A. L. & Bayot, A. Mitochondrial proteases and cancer. Biochim. Biophys. Acta 1807, 595–601 (2011).

    CAS  PubMed  Google Scholar 

  9. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Google Scholar 

  10. Quesada, V., Ordonez, G. R., Sanchez, L. M., Puente, X. S. & López-Otín, C. The degradome database: mammalian proteases and diseases of proteolysis. Nucleic Acids Res. 37, D239–D243 (2009).

    CAS  PubMed  Google Scholar 

  11. Rawlings, N. D., Waller, M., Barrett, A. J. & Bateman, A. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 42, D503–D509 (2014).

    CAS  PubMed  Google Scholar 

  12. Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kremmidiotis, G. et al. Molecular and functional analyses of the human and mouse genes encoding AFG3L1, a mitochondrial metalloprotease homologous to the human spastic paraplegia protein. Genomics 76, 58–65 (2001).

    CAS  PubMed  Google Scholar 

  14. Voos, W. Chaperone-protease networks in mitochondrial protein homeostasis. Biochim. Biophys. Acta 1833, 388–399 (2013).

    CAS  PubMed  Google Scholar 

  15. Schmidt, O., Pfanner, N. & Meisinger, C. Mitochondrial protein import: from proteomics to functional mechanisms. Nature Rev. Mol. Cell Biol. 11, 655–667 (2010). This excellent review describes various components and pathways that are involved in mitochondrial import.

    CAS  Google Scholar 

  16. Gakh, O., Cavadini, P. & Isaya, G. Mitochondrial processing peptidases. Biochim. Biophys. Acta 1592, 63–77 (2002).

    CAS  PubMed  Google Scholar 

  17. Teixeira, P. F. & Glaser, E. Processing peptidases in mitochondria and chloroplasts. Biochim. Biophys. Acta 1833, 360–370 (2013).

    CAS  PubMed  Google Scholar 

  18. Dvorakova-Hola, K. et al. Glycine-rich loop of mitochondrial processing peptidase α-subunit is responsible for substrate recognition by a mechanism analogous to mitochondrial receptor Tom20. J. Mol. Biol. 396, 1197–1210 (2010).

    CAS  PubMed  Google Scholar 

  19. Nunnari, J., Fox, T. D. & Walter, P. A mitochondrial protease with two catalytic subunits of nonoverlapping specificities. Science 262, 1997–2004 (1993).

    CAS  PubMed  Google Scholar 

  20. Ieva, R. et al. Mitochondrial inner membrane protease promotes assembly of presequence translocase by removing a carboxy-terminal targeting sequence. Nature Commun. 4, 2853 (2013).

    Google Scholar 

  21. Vogtle, F. N. et al. Mitochondrial protein turnover: role of the precursor intermediate peptidase Oct1 in protein stabilization. Mol. Biol. Cell 22, 2135–2143 (2011).

    PubMed  PubMed Central  Google Scholar 

  22. Vogtle, F. N. et al. Global analysis of the mitochondrial N-proteome identifies a processing peptidase critical for protein stability. Cell 139, 428–439 (2009).

    PubMed  Google Scholar 

  23. Serero, A., Giglione, C., Sardini, A., Martinez-Sanz, J. & Meinnel, T. An unusual peptide deformylase features in the human mitochondrial N-terminal methionine excision pathway. J. Biol. Chem. 278, 52953–52963 (2003).

    CAS  PubMed  Google Scholar 

  24. Gerdes, F., Tatsuta, T. & Langer, T. Mitochondrial AAA proteases — towards a molecular understanding of membrane-bound proteolytic machines. Biochim. Biophys. Acta 1823, 49–55 (2012).

    CAS  PubMed  Google Scholar 

  25. Koppen, M., Metodiev, M. D., Casari, G., Rugarli, E. I. & Langer, T. Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia. Mol. Cell. Biol. 27, 758–767 (2007).

    CAS  PubMed  Google Scholar 

  26. Stiburek, L. et al. YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation. Mol. Biol. Cell 23, 1010–1023 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hornig-Do, H. T. et al. Nonsense mutations in the COX1 subunit impair the stability of respiratory chain complexes rather than their assembly. EMBO J. 31, 1293–1307 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zurita Rendon, O. & Shoubridge, E. A. Early complex I assembly defects result in rapid turnover of the ND1 subunit. Hum. Mol. Genet. 21, 3815–3824 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lu, B. et al. The ATP-dependent Lon protease of Mus musculus is a DNA-binding protein that is functionally conserved between yeast and mammals. Gene 306, 45–55 (2003).

    CAS  PubMed  Google Scholar 

  30. Venkatesh, S., Lee, J., Singh, K., Lee, I. & Suzuki, C. K. Multitasking in the mitochondrion by the ATP-dependent Lon protease. Biochim. Biophys. Acta 1823, 56–66 (2012).

    CAS  PubMed  Google Scholar 

  31. Teng, H. et al. Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease. Proc. Natl Acad. Sci. USA 110, 12679–12684 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bezawork-Geleta, A., Saiyed, T., Dougan, D. A. & Truscott, K. N. Mitochondrial matrix proteostasis is linked to hereditary paraganglioma: LON-mediated turnover of the human flavinylation factor SDH5 is regulated by its interaction with SDHA. FASEB J. 28, 1794–1804 (2014).

    CAS  PubMed  Google Scholar 

  33. Kita, K., Suzuki, T. & Ochi, T. Diphenylarsinic acid promotes degradation of glutaminase C by mitochondrial Lon protease. J. Biol. Chem. 287, 18163–18172 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Fukuda, R. et al. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129, 111–122 (2007).

    CAS  PubMed  Google Scholar 

  35. Bota, D. A. & Davies, K. J. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nature Cell Biol. 4, 674–680 (2002).

    CAS  PubMed  Google Scholar 

  36. Granot, Z. et al. Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors. Mol. Endocrinol. 21, 2164–2177 (2007).

    CAS  PubMed  Google Scholar 

  37. Tian, Q. et al. Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells. J. Biol. Chem. 286, 26424–26430 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Matsushima, Y., Goto, Y. & Kaguni, L. S. Mitochondrial Lon protease regulates mitochondrial DNA copy number and transcription by selective degradation of mitochondrial transcription factor A (TFAM). Proc. Natl Acad. Sci. USA 107, 18410–18415 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Quirós, P. M. et al. ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep. 8, 542–556 (2014).

    PubMed  Google Scholar 

  40. Haynes, C. M., Petrova, K., Benedetti, C., Yang, Y. & Ron, D. ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Dev. Cell 13, 467–480 (2007). This paper describes the key role of the mitoprotease CLPP in the UPRmt.

    CAS  PubMed  Google Scholar 

  41. Gispert, S. et al. Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors. Hum. Mol. Genet. 22, 4871–4887 (2013).

    CAS  PubMed  Google Scholar 

  42. Stahl, A. et al. Isolation and identification of a novel mitochondrial metalloprotease (PreP) that degrades targeting presequences in plants. J. Biol. Chem. 277, 41931–41939 (2002).

    CAS  PubMed  Google Scholar 

  43. Kambacheld, M., Augustin, S., Tatsuta, T., Muller, S. & Langer, T. Role of the novel metallopeptidase Mop112 and saccharolysin for the complete degradation of proteins residing in different subcompartments of mitochondria. J. Biol. Chem. 280, 20132–20139 (2005).

    CAS  PubMed  Google Scholar 

  44. Mossmann, D. et al. Amyloid-β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation. Cell Metab. 20, 662–669 (2014). This paper identifies a possible mechanism linking Alzheimer disease with mitochondrial dysfunction caused by defects in a mitoprotease.

    CAS  PubMed  Google Scholar 

  45. Falkevall, A. et al. Degradation of the amyloid β-protein by the novel mitochondrial peptidasome, PreP. J. Biol. Chem. 281, 29096–29104 (2006).

    CAS  PubMed  Google Scholar 

  46. Serizawa, A., Dando, P. M. & Barrett, A. J. Characterization of a mitochondrial metallopeptidase reveals neurolysin as a homologue of thimet oligopeptidase. J. Biol. Chem. 270, 2092–2098 (1995).

    CAS  PubMed  Google Scholar 

  47. Clausen, T., Kaiser, M., Huber, R. & Ehrmann, M. HTRA proteases: regulated proteolysis in protein quality control. Nature Rev. Mol. Cell Biol. 12, 152–162 (2011).

    CAS  Google Scholar 

  48. Plun-Favreau, H. et al. HtrA2 deficiency causes mitochondrial uncoupling through the F1F0-ATP synthase and consequent ATP depletion. Cell Death Dis. 3, e335 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Osman, C., Wilmes, C., Tatsuta, T. & Langer, T. Prohibitins interact genetically with Atp23, a novel processing peptidase and chaperone for the F1F0-ATP synthase. Mol. Biol. Cell 18, 627–635 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Potting, C., Wilmes, C., Engmann, T., Osman, C. & Langer, T. Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35. EMBO J. 29, 2888–2898 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Almajan, E. R. et al. AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J. Clin. Invest. 122, 4048–4058 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Nolden, M. et al. The m-AAA protease defective in hereditary spastic paraplegia controls ribosome assembly in mitochondria. Cell 123, 277–289 (2005).

    CAS  PubMed  Google Scholar 

  53. Maltecca, F. et al. Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. J. Clin. Invest. 125, 263–274 (2015).

    PubMed  Google Scholar 

  54. Rainbolt, T. K., Atanassova, N., Genereux, J. C. & Wiseman, R. L. Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation. Cell Metab. 18, 908–919 (2013). This paper illustrates the function of a mitoprotease regulating mitochondrial protein synthesis under stress conditions.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Potting, C. et al. TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid. Cell Metab. 18, 287–295 (2013).

    CAS  PubMed  Google Scholar 

  56. Lu, B. et al. Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Mol. Cell 49, 121–132 (2013).

    CAS  PubMed  Google Scholar 

  57. Liu, T. et al. DNA and RNA binding by the mitochondrial Lon protease is regulated by nucleotide and protein substrate. J. Biol. Chem. 279, 13902–13910 (2004).

    CAS  PubMed  Google Scholar 

  58. Goo, H. G., Jung, M. K., Han, S. S., Rhim, H. & Kang, S. HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA. Biochim. Biophys. Acta 1833, 1866–1875 (2013).

    CAS  PubMed  Google Scholar 

  59. Oberto, J. et al. Qri7/OSGEPL, the mitochondrial version of the universal Kae1/YgjD protein, is essential for mitochondrial genome maintenance. Nucleic Acids Res. 37, 5343–5352 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Polianskyte, Z. et al. LACTB is a filament-forming protein localized in mitochondria. Proc. Natl Acad. Sci. USA 106, 18960–18965 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Houtkooper, R. H. et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451–457 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Runkel, E. D., Liu, S., Baumeister, R. & Schulze, E. Surveillance-activated defenses block the ROS-induced mitochondrial unfolded protein response. PLoS Genet. 9, e1003346 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhao, Q. et al. A mitochondrial specific stress response in mammalian cells. EMBO J. 21, 4411–4419 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Jovaisaite, V., Mouchiroud, L. & Auwerx, J. The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease. J. Exp. Biol. 217, 137–143 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M. & Haynes, C. M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587–590 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Aldridge, J. E., Horibe, T. & Hoogenraad, N. J. Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements. PLoS ONE 2, e874 (2007).

    PubMed  PubMed Central  Google Scholar 

  67. Wu, Y. et al. Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population. Cell 158, 1415–1430 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Bahat, A. et al. StAR enhances transcription of genes encoding the mitochondrial proteases involved in its own degradation. Mol. Endocrinol. 28, 208–224 (2014).

    PubMed  Google Scholar 

  69. Moisoi, N. et al. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ. 16, 449–464 (2009). References 68 and 69 identify new stress response pathways in mitochondria.

    CAS  PubMed  Google Scholar 

  70. Friedman, J. R. & Nunnari, J. Mitochondrial form and function. Nature 505, 335–343 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Mishra, P. & Chan, D. C. Mitochondrial dynamics and inheritance during cell division, development and disease. Nature Rev. Mol. Cell Biol. 15, 634–646 (2014). This is an outstanding review of processes that are implicated in mitochondrial dynamics in both normal and pathological conditions.

    CAS  Google Scholar 

  72. Anand, R. et al. The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J. Cell Biol. 204, 919–929 (2014). This paper describes mitoproteases that are involved in the processing of OPA1.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Ishihara, N., Fujita, Y., Oka, T. & Mihara, K. Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J. 25, 2966–2977 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Sood, A. et al. A Mitofusin-2-dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver. Proc. Natl Acad. Sci. USA 111, 16017–16022 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Mishra, P., Carelli, V., Manfredi, G. & Chan, D. C. Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab. 19, 630–641 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Ehses, S. et al. Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J. Cell Biol. 187, 1023–1036 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Quirós, P. M. et al. Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. EMBO J. 31, 2117–2133 (2012).

    PubMed  PubMed Central  Google Scholar 

  78. Head, B., Griparic, L., Amiri, M., Gandre-Babbe, S. & van der Bliek, A. M. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J. Cell Biol. 187, 959–966 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Quirós, P. M., Ramsay, A. J. & López-Otín, C. New roles for OMA1 metalloprotease: from mitochondrial proteostasis to metabolic homeostasis. Adipocyte 2, 7–11 (2013).

    PubMed  PubMed Central  Google Scholar 

  80. Escobar-Henriques, M. & Langer, T. Dynamic survey of mitochondria by ubiquitin. EMBO Rep. 15, 231–243 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Yue, W. et al. A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res. 24, 482–496 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Nakamura, N. & Hirose, S. Regulation of mitochondrial morphology by USP30, a deubiquitinating enzyme present in the mitochondrial outer membrane. Mol. Biol. Cell 19, 1903–1911 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nature Rev. Mol. Cell Biol. 12, 9–14 (2011).

    CAS  Google Scholar 

  84. Jin, S. M. & Youle, R. J. The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy 9, 1750–1757 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Greene, A. W. et al. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 13, 378–385 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Jin, S. M. et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191, 933–942 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Thomas, R. E., Andrews, L. A., Burman, J. L., Lin, W. Y. & Pallanck, L. J. PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS Genet. 10, e1004279 (2014). References 85–87 identify the mitoproteases that are involved in PINK1 processing and degradation.

    PubMed  PubMed Central  Google Scholar 

  88. Cilenti, L. et al. Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy. Biochim. Biophys. Acta 1843, 1295–1307 (2014).

    CAS  PubMed  Google Scholar 

  89. Park, H. M. et al. The serine protease HtrA2/Omi cleaves Parkin and irreversibly inactivates its E3 ubiquitin ligase activity. Biochem. Biophys. Res. Commun. 387, 537–542 (2009).

    CAS  PubMed  Google Scholar 

  90. Xiong, H. et al. Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J. Clin. Invest. 119, 650–660 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Sekine, S. et al. Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. J. Biol. Chem. 287, 34635–34645 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Chen, G. et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol. Cell 54, 362–377 (2014).

    CAS  PubMed  Google Scholar 

  93. Wang, Z., Jiang, H., Chen, S., Du, F. & Wang, X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148, 228–243 (2012).

    CAS  PubMed  Google Scholar 

  94. MacVicar, T. D. & Lane, J. D. Impaired OMA1-dependent cleavage of OPA1 and reduced DRP1 fission activity combine to prevent mitophagy in cells that are dependent on oxidative phosphorylation. J. Cell Sci. 127, 2313–2325 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Wang, K., Jin, M., Liu, X. & Klionsky, D. J. Proteolytic processing of Atg32 by the mitochondrial i-AAA protease Yme1 regulates mitophagy. Autophagy 9, 1828–1836 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Bingol, B. et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 (2014). This paper reports the crucial function of a mitochondrial isopeptidase in the regulation of parkin-mediated mitophagy.

    CAS  PubMed  Google Scholar 

  97. Mariño, G., Niso-Santano, M., Baehrecke, E. H. & Kroemer, G. Self-consumption: the interplay of autophagy and apoptosis. Nature Rev. Mol. Cell Biol. 15, 81–94 (2014).

    Google Scholar 

  98. Jiang, X., Jiang, H., Shen, Z. & Wang, X. Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis. Proc. Natl Acad. Sci. USA 111, 14782–14787 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Baker, M. J. et al. Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics. EMBO J. 33, 578–593 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Xiao, X. et al. OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in experimental models of ischemic kidney injury. Am. J. Physiol. Renal Physiol. 306, F1318–F1326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Chao, J. R. et al. Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 452, 98–102 (2008).

    CAS  PubMed  Google Scholar 

  102. Suzuki, Y. et al. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol. Cell 8, 613–621 (2001).

    CAS  PubMed  Google Scholar 

  103. Hartkamp, J., Carpenter, B. & Roberts, S. G. The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi. Mol. Cell 37, 159–171 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Sosna, J. et al. The proteases HtrA2/Omi and UCH-L1 regulate TNF-induced necroptosis. Cell Commun. Signal. 11, 76 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Yacobi-Sharon, K., Namdar, Y. & Arama, E. Alternative germ cell death pathway in Drosophila involves HtrA2/Omi, lysosomes, and a caspase-9 counterpart. Dev. Cell 25, 29–42 (2013).

    CAS  PubMed  Google Scholar 

  106. Cipolat, S. et al. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126, 163–175 (2006).

    CAS  PubMed  Google Scholar 

  107. Frezza, C. et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177–189 (2006).

    CAS  PubMed  Google Scholar 

  108. Bratic, A. & Larsson, N. G. The role of mitochondria in aging. J. Clin. Invest. 123, 951–957 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Baker, B. M. & Haynes, C. M. Mitochondrial protein quality control during biogenesis and aging. Trends Biochem. Sci. 36, 254–261 (2011).

    CAS  PubMed  Google Scholar 

  110. Lionaki, E. & Tavernarakis, N. Oxidative stress and mitochondrial protein quality control in aging. J. Proteomics 92, 181–194 (2013).

    CAS  PubMed  Google Scholar 

  111. Ngo, J. K. & Davies, K. J. Importance of the Lon protease in mitochondrial maintenance and the significance of declining Lon in aging. Ann. N.Y. Acad. Sci. 1119, 78–87 (2007).

    CAS  PubMed  Google Scholar 

  112. Ngo, J. K., Pomatto, L. C. & Davies, K. J. Upregulation of the mitochondrial Lon protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging. Redox Biol. 1, 258–264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Erjavec, N. et al. Deletion of the mitochondrial Pim1/Lon protease in yeast results in accelerated aging and impairment of the proteasome. Free Radic. Biol. Med. 56, 9–16 (2013).

    CAS  PubMed  Google Scholar 

  114. Luce, K. & Osiewacz, H. D. Increasing organismal healthspan by enhancing mitochondrial protein quality control. Nature Cell Biol. 11, 852–858 (2009).

    CAS  PubMed  Google Scholar 

  115. Fischer, F., Weil, A., Hamann, A. & Osiewacz, H. D. Human CLPP reverts the longevity phenotype of a fungal ClpP deletion strain. Nature Commun. 4, 1397 (2013).

    Google Scholar 

  116. Kang, S. et al. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. Cell Death Differ. 20, 259–269 (2013). References 113–116 identify some mitoproteases that are involved in the modulation of ageing and longevity.

    CAS  PubMed  Google Scholar 

  117. Maltecca, F. et al. The mitochondrial protease AFG3L2 is essential for axonal development. J. Neurosci. 28, 2827–2836 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. López, L. M. et al. Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts. Eur. J. Hum. Genet. 20, 341–347 (2012).

    PubMed  Google Scholar 

  119. Lu, B. et al. A mutation in the inner mitochondrial membrane peptidase 2-like gene (Immp2l) affects mitochondrial function and impairs fertility in mice. Biol. Reprod. 78, 601–610 (2008).

    CAS  PubMed  Google Scholar 

  120. George, S. K., Jiao, Y., Bishop, C. E. & Lu, B. Mitochondrial peptidase IMMP2L mutation causes early onset of age-associated disorders and impairs adult stem cell self-renewal. Aging Cell 10, 584–594 (2011).

    CAS  PubMed  Google Scholar 

  121. George, S. K., Jiao, Y., Bishop, C. E. & Lu, B. Oxidative stress is involved in age-dependent spermatogenic damage of Immp2l mutant mice. Free Radic. Biol. Med. 52, 2223–2233 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Stames, E. M. & O'Toole, J. F. Mitochondrial aminopeptidase deletion increases chronological lifespan and oxidative stress resistance while decreasing respiratory metabolism in S. cerevisiae. PLoS ONE 8, e77234 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Koopman, W. J., Willems, P. H. & Smeitink, J. A. Monogenic mitochondrial disorders. N. Engl. J. Med. 366, 1132–1141 (2012).

    CAS  PubMed  Google Scholar 

  124. Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259 (2003).

    CAS  PubMed  Google Scholar 

  125. Strauss, K. M. et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum. Mol. Genet. 14, 2099–2111 (2005).

    CAS  PubMed  Google Scholar 

  126. Unal Gulsuner, H. et al. Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease. Proc. Natl Acad. Sci. USA 111, 18285–18290 (2014). References 124–126 describe some examples of mitoproteases that are associated with Parkinson disease.

    PubMed  PubMed Central  Google Scholar 

  127. Jones, J. M. et al. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of Mnd2 mutant mice. Nature 425, 721–727 (2003).

    CAS  PubMed  Google Scholar 

  128. Martins, L. M. et al. Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol. Cell. Biol. 24, 9848–9862 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Shi, G. et al. Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease. Hum. Mol. Genet. 20, 1966–1974 (2011).

    CAS  PubMed  Google Scholar 

  130. Yoshioka, H. et al. The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia. J. Cereb. Blood Flow Metab. 33, 1658–1665 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Bertelsen, B. et al. Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome. Eur. J. Hum. Genet. 22, 1283–1289 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Casey, J. P. et al. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum. Genet. 131, 565–579 (2012).

    PubMed  Google Scholar 

  133. Gimelli, S. et al. Interstitial 7q31.1 copy number variations disrupting IMMP2L gene are associated with a wide spectrum of neurodevelopmental disorders. Mol. Cytogenet. 7, 54 (2014).

    PubMed  PubMed Central  Google Scholar 

  134. Di Bella, D. et al. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nature Genet. 42, 313–321 (2010).

    CAS  PubMed  Google Scholar 

  135. Pierson, T. M. et al. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet. 7, e1002325 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Casari, G. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983 (1998).

    CAS  PubMed  Google Scholar 

  137. Pfeffer, G. et al. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain 137, 1323–1336 (2014).

    PubMed  PubMed Central  Google Scholar 

  138. Wedding, I. M. et al. Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions. PLoS ONE 9, e86340 (2014). References 134–138 describe human diseases that are caused by mutations in genes encoding AAA proteases.

    PubMed  PubMed Central  Google Scholar 

  139. Ferreirinha, F. et al. Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. J. Clin. Invest. 113, 231–242 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Martinelli, P. et al. Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration. Hum. Mol. Genet. 18, 2001–2013 (2009).

    CAS  PubMed  Google Scholar 

  141. Kondadi, A. K. et al. Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation. EMBO J. 33, 1011–1026 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Maltecca, F. et al. Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration. J. Neurosci. 29, 9244–9254 (2009). References 53 and 139–142 illustrate the key roles of mitoproteases in neuronal function.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Almontashiri, N. A. et al. SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell Rep. 7, 834–847 (2014).

    CAS  PubMed  Google Scholar 

  144. Civitarese, A. E. et al. Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease PARL. Cell Metab. 11, 412–426 (2010).

    CAS  PubMed  Google Scholar 

  145. Cavalcanti, D. M. et al. Neurolysin knockout mice generation and initial phenotype characterization. J. Biol. Chem. 289, 15426–15440 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Strauss, K. A. et al. CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. Am. J. Hum. Genet. 96, 121–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Jenkinson, E. M. et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am. J. Hum. Genet. 92, 605–613 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Miyake, N. et al. Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation. Hum. Mutat. 34, 446–452 (2013).

    CAS  PubMed  Google Scholar 

  150. O'Toole, J. F. et al. Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J. Clin. Invest. 120, 791–802 (2010). References 147–150 describe several examples of human diseases that are caused by mutations in genes encoding mitoproteases.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  152. Wallace, D. C. Mitochondria and cancer. Nature Rev. Cancer 12, 685–698 (2012).

    CAS  Google Scholar 

  153. Nie, X. et al. Down-regulating overexpressed human Lon in cervical cancer suppresses cell proliferation and bioenergetics. PLoS ONE 8, e81084 (2013).

    PubMed  PubMed Central  Google Scholar 

  154. Cheng, C. W. et al. Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species. Cell Death Dis. 4, e681 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Gibellini, L. et al. Silencing of mitochondrial Lon protease deeply impairs mitochondrial proteome and function in colon cancer cells. FASEB J. 28, 5122–5135 (2014).

    CAS  PubMed  Google Scholar 

  156. Bayot, A. et al. Effect of Lon protease knockdown on mitochondrial function in HeLa cells. Biochimie 100, 38–47 (2014).

    CAS  PubMed  Google Scholar 

  157. Bernstein, S. H. et al. The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood 119, 3321–3329 (2012). This is an excellent example of inhibition of a mitoprotease as a new strategy for cancer treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Quirós, P. M., Bárcena, C. & López-Otín, C. Lon protease: a key enzyme controlling mitochondrial bioenergetics in cancer. Mol. Cell. Oncol. 1, e968505 (2014).

    PubMed  PubMed Central  Google Scholar 

  159. Yamauchi, S. et al. p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion. J. Cell Biol. 204, 1191–1207 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Kong, B., Wang, Q., Fung, E., Xue, K. & Tsang, B. K. p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers. J. Biol. Chem. 289, 27134–27145 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Leszczyniecka, M. et al. MAP1D, a novel methionine aminopeptidase family member is overexpressed in colon cancer. Oncogene 25, 3471–3478 (2006).

    CAS  PubMed  Google Scholar 

  162. Kohler, A. et al. Genome-wide association study on differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 98, E1674–E1681 (2013).

    PubMed  Google Scholar 

  163. Alikhani, N. et al. Targeting capacity and conservation of PreP homologues localization in mitochondria of different species. J. Mol. Biol. 410, 400–410 (2011).

    CAS  PubMed  Google Scholar 

  164. Canet-Aviles, R. M. et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl Acad. Sci. USA 101, 9103–9108 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Smith, P. M., Fox, J. L. & Winge, D. R. Biogenesis of the cytochrome bc1 complex and role of assembly factors. Biochim. Biophys. Acta 1817, 276–286 (2012).

    CAS  PubMed  Google Scholar 

  166. Miyakoshi, K. et al. The identification of novel ovarian proteases through the use of genomic and bioinformatic methodologies. Biol. Reprod. 75, 823–835 (2006).

    CAS  PubMed  Google Scholar 

  167. Smith, M. A. & Schnellmann, R. G. Calpains, mitochondria, and apoptosis. Cardiovasc. Res. 96, 32–37 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Arrington, D. D., Van Vleet, T. R. & Schnellmann, R. G. Calpain 10: a mitochondrial calpain and its role in calcium-induced mitochondrial dysfunction. Am. J. Physiol. Cell Physiol. 291, C1159–C1171 (2006).

    CAS  PubMed  Google Scholar 

  169. Krumschnabel, G., Sohm, B., Bock, F., Manzl, C. & Villunger, A. The enigma of caspase-2: the laymen's view. Cell Death Differ. 16, 195–207 (2009).

    CAS  PubMed  Google Scholar 

  170. Lakhani, S. A. et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311, 847–851 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Kantari, C. & Walczak, H. Caspase-8 and bid: caught in the act between death receptors and mitochondria. Biochim. Biophys. Acta 1813, 558–563 (2011).

    CAS  PubMed  Google Scholar 

  172. Costantini, P. et al. Pre-processed caspase-9 contained in mitochondria participates in apoptosis. Cell Death Differ. 9, 82–88 (2002).

    CAS  PubMed  Google Scholar 

  173. Durcan, T. M. et al. USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin. EMBO J. 33, 2473–2491 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Schwickart, M. et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463, 103–107 (2010).

    CAS  PubMed  Google Scholar 

  175. Cornelissen, T. et al. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum. Mol. Genet. 23, 5227–5242 (2014).

    CAS  PubMed  Google Scholar 

  176. Fu, J. et al. Disruption of SUMO-specific protease 2 induces mitochondria mediated neurodegeneration. PLoS Genet. 10, e1004579 (2014).

    PubMed  PubMed Central  Google Scholar 

  177. Zunino, R., Schauss, A., Rippstein, P., Andrade-Navarro, M. & McBride, H. M. The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J. Cell Sci. 120, 1178–1188 (2007).

    CAS  PubMed  Google Scholar 

  178. Betin, V. M., MacVicar, T. D., Parsons, S. F., Anstee, D. J. & Lane, J. D. A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress. Autophagy 8, 664–676 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Leissring, M. A. et al. Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem. J. 383, 439–446 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Chow, K. M., Ma, Z., Cai, J., Pierce, W. M. & Hersh, L. B. Nardilysin facilitates complex formation between mitochondrial malate dehydrogenase and citrate synthase. Biochim. Biophys. Acta 1723, 292–301 (2005).

    CAS  PubMed  Google Scholar 

  181. Martinvalet, D., Dykxhoorn, D. M., Ferrini, R. & Lieberman, J. Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell 133, 681–692 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Han, J. et al. Deregulation of mitochondrial membrane potential by mitochondrial insertion of granzyme B and direct Hax-1 cleavage. J. Biol. Chem. 285, 22461–22472 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank all members of their laboratories for their comments and apologize for omission of relevant works due to space constraints. T.L. is supported by grants from the European Research Council, the German Research Council and the Max Planck Society. C.L-O. is supported by grants from Ministerio de Economía y Competitividad, Spain, and is an Investigator of the Botin Foundation supported by Banco Santander through its Santander Universities Global Division. The Instituto Universitario de Oncología is supported by Obra Social Cajastur and Acción Transversal del Cáncer (Red Temática Investigación Cooperativa en Cáncer).

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FURTHER INFORMATION

Degradome

MEROPS

MitoCarta

Online Mendelian Inheritance in Man (OMIM)

Glossary

Degradome

The complete repertoire of proteases that are produced by a cell, tissue or organism.

Mitochondrial DNA

(mtDNA). A circular 16.6 kb DNA molecule that is located in the matrix of a mitochondrion, which encodes 13 proteins, 22 tRNAs and 2 rRNAs that are required for a functional oxidative phosphorylation system.

Reactive oxygen species

(ROS). Reactive molecules that are formed within the cell and generated by the reduction of oxygen with a single electron (superoxides), two electrons (hydrogen peroxide) or three electrons (hydroxyl radicals).

ATPases associated with diverse cellular activities

(AAA). A large family of structurally conserved ATPases that share a common conserved module of 230 amino acid residues, in which assembly of the ATPase active site requires subunit oligomerization.

Pseudogenization

A process through which genes lose their ability to encode proteins, either by mutation or by loss of expression.

Oxidative phosphorylation

(OXPHOS). A biochemical pathway in mitochondria that generates ATP through the use of reducing equivalents of hydrogen in the form of NADH and FADH2, which are produced by the oxidation of nutrients.

Cristae

Invaginations of the mitochondrial inner membrane.

Deubiquitylase

One of a large family of enzymes comprising Cys proteases and metalloproteases that remove conjugated ubiquitin from proteins and are linked to the regulation and termination of ubiquitin-mediated signalling.

E3 ubiquitin-protein ligases

Enzymes that catalyse the final step of the process that activates and transfers ubiquitin and ubiquitin-like molecules to substrate proteins.

Mitochondrial outer membrane permeabilization

(MOMP). An apoptosis-associated process that results in the release of apoptosis-inducing proteins (such as cytochrome c, apoptosis-inducing factor (AIF), second mitochondria-derived activator of caspase (SMAC) and others) from the mitochondrial intermembrane space through the outer membrane into the cytosol.

Purkinje cells

Inhibitory neurons in the cerebellum that use GABA (γ-aminobutyric acid) as their neurotransmitter. Their cell bodies are situated below the molecular layer, and their dendrites branch extensively into this layer. Their axons project into the underlying white matter and provide the only output from the cerebellar cortex.

Mitohormesis

A process in which low levels of mitochondrial stress, such as that caused by reactive oxygen species, result in a large, diverse cytosolic and nuclear response that induces a protective state instead of a harmful response, reducing susceptibility to disease and potentially promoting longevity.

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Quirós, P., Langer, T. & López-Otín, C. New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol 16, 345–359 (2015). https://doi.org/10.1038/nrm3984

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