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Mechanisms of mitochondrial respiratory adaptation

Nature Reviews Molecular Cell Biology volume 23, pages 817–835 (2022)Cite this article

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Abstract

Mitochondrial energetic adaptations encompass a plethora of conserved processes that maintain cell and organismal fitness and survival in the changing environment by adjusting the respiratory capacity of mitochondria. These mitochondrial responses are governed by general principles of regulatory biology exemplified by changes in gene expression, protein translation, protein complex formation, transmembrane transport, enzymatic activities and metabolite levels. These changes can promote mitochondrial biogenesis and membrane dynamics that in turn support mitochondrial respiration. The main regulatory components of mitochondrial energetic adaptation include: the transcription coactivator peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC1α) and associated transcription factors; mTOR and endoplasmic reticulum stress signalling; TOM70-dependent mitochondrial protein import; the cristae remodelling factors, including mitochondrial contact site and cristae organizing system (MICOS) and OPA1; lipid remodelling; and the assembly and metabolite-dependent regulation of respiratory complexes. These adaptive molecular and structural mechanisms increase respiration to maintain basic processes specific to cell types and tissues. Failure to execute these regulatory responses causes cell damage and inflammation or senescence, compromising cell survival and the ability to adapt to energetically demanding conditions. Thus, mitochondrial adaptive cellular processes are important for physiological responses, including to nutrient availability, temperature and physical activity, and their failure leads to diseases associated with mitochondrial dysfunction such as metabolic and age-associated diseases and cancer.

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Fig. 1: Regulation of mitochondrial respiratory capacity.
Fig. 2: Transcriptional control of mitochondrial biogenesis through PGC1α.
Fig. 3: Translational control of mitochondrial respiratory chain assembly.
Fig. 4: Post-translational mechanisms governing respiratory control and the role of mitochondrial membrane dynamics.

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Acknowledgements

This work was partially supported by grants from the US National Institutes of Health R01 DK089883 (NIDDK), R01 DK081418 (NIDDK), R01 DK117655 (NIDDK), R01 CA181217 (NCI), 9R56 AG074527 (NIA), R01 GM121452 (NIGMS), and the Claudia Adams Barr Award to P.P. F32 GM125243 (NIGMS) and the Charles A. King Trust Postdoctoral Fellowship Program were awarded to C.F.B. P.L.-M. is supported by the Human Frontier Science Program (LT-000033/2019-L).

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  1. These authors contributed equally: Christopher F. Bennett, Pedro Latorre-Muro.

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    Christopher F. Bennett, Pedro Latorre-Muro & Pere Puigserver

  2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Christopher F. Bennett, Pedro Latorre-Muro & Pere Puigserver

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  1. Christopher F. Bennett
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C.F.B., P.L.-M. and P.P. contributed substantially to discussion of the content, writing of the article and editing of the manuscript before submission.

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Correspondence to Pere Puigserver.

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Glossary

Cristae

Invaginations of the inner mitochondrial membrane that increase the surface area of respiratory reactions and harbour the respiratory complexes.

Brown and beige adipose tissues

Thermogenic fat cells with abundant mitochondria that oxidize glucose, fatty acids and branched-chain amino acids to generate heat.

Uncoupling protein 1

(UCP1). Inner mitochondrial membrane protein expressed in thermogenic tissues that dissipates membrane potential from the respiratory complexes and sustains thermogenesis.

Haem

Porphyrin group coordinating an iron atom required for electron transfer or oxygen transport.

Iron–sulfur clusters

Iron sulfide molecules that transfer electrons across respiratory complexes.

ER stress

A condition that occurs when the capacity of the endoplasmic reticulum (ER) lumen to fold proteins is saturated. ER stress transduces signals to other organelles such as mitochondria to adapt cellular metabolism to satisfy energy demands.

Mediator complex

A multiprotein complex that transduces signals from transcription factors to RNA polymerase II to control gene expression.

Nuclear receptors

Ligand-regulated transcription factors that are activated by steroid hormones and other lipid-related molecules.

Catecholamines

A group of chemical neurotransmitters, including dopamine, adrenaline and noradrenaline, that are released into the blood upon stress and modulate beige and brown fat tissue activity.

mTOR

Mammalian target of rapamycin, a nutrient-sensor kinase involved in the control of cellular growth, survival, metabolism and immunity.

AMPK

AMP-activated protein kinase that senses fluctuations in the ATP/AMP ratio.

AKT

Also known as protein kinase B (PKB), a group of serine/threonine kinases that respond to a myriad of external stimuli and include AKT1, AKT2 and AKT3.

Translation initiator of short 5′ UTR (TISU) elements

Sequence elements that are downstream of transcription start sites and regulate both transcriptional and translational initiation and are present in mRNAs with very short 5′ untranslated regions (UTRs).

PINK1–parkin mitophagy pathway

A quality control pathway that marks damaged mitochondria to promote their autophagy-mediated destruction.

Branched-chain amino acids

Amino acids, including valine, leucine and isoleucine, that can be oxidized in the cell to obtain energy.

Unfolded protein response

A process that regulates a transcriptional and translational response to endoplasmic reticulum protein folding stress.

Internal mitochondrial targeting sequence-like signals

Peptide sequences present within proteins destined for mitochondria that interact with import receptors and increase import competence.

SEC translocon

Protein complex embedded in the endoplasmic reticulum membrane that transports proteins from and through the endoplasmic reticulum lumen.

ADP/ATP carrier

An inner mitochondrial membrane transporter that exchanges ATP/ADP.

Phosphate carrier

An inner mitochondrial membrane transporter of phosphate.

AAA+ proteases

Subset of ATPase proteases that participate in diverse quality control mechanisms in mitochondria and the cytosol (26S proteasome).

Substrate channelling

Biochemical phenomenon whereby the intermediate product from one enzyme is shuttled as a substrate to the next enzyme before equilibration with the bulk aqueous solvent. This model is contested for mitochondrial respiratory supercomplexes, but refers to the presence of functionally distinct pools of ubiquinone or cytochrome c within supercomplexess that pass between complex I and complex III2 or complex III2 and complex IV, respectively.

Sphingolipids

A class of phospholipids containing a sphingosine backbone. Sphingolipids facilitate mitochondrial function and cellular signalling responses, but their accumulation correlates with mitochondrial dysfunction and chronic metabolic diseases such as type 2 diabetes.

sn-1 position

The first stereochemical position on a glycerol moiety to which a fatty acid is attached.

Barth syndrome

A rare X-linked genetic disorder of cardiolipin metabolism that presents with cardiomyopathy, neutropenia and muscle weakness.

Substantia nigra

Basal ganglia structure in the brain that plays important roles in behaviour–reward neuronal programmes.

Sengers syndrome

A rare autosomal condition characterized by myocardiopathy, lactic acidosis, muscle weakness and short life expectancy.

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Bennett, C.F., Latorre-Muro, P. & Puigserver, P. Mechanisms of mitochondrial respiratory adaptation. Nat Rev Mol Cell Biol 23, 817–835 (2022). https://doi.org/10.1038/s41580-022-00506-6

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