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Quality control of the mitochondrial proteome

Abstract

Mitochondria contain about 1,000–1,500 proteins that fulfil multiple functions. Mitochondrial proteins originate from two genomes: mitochondrial and nuclear. Hence, proper mitochondrial function requires synchronization of gene expression in the nucleus and in mitochondria and necessitates efficient import of mitochondrial proteins into the organelle from the cytosol. Furthermore, the mitochondrial proteome displays high plasticity to allow the adaptation of mitochondrial function to cellular requirements. Maintenance of this complex and adaptable mitochondrial proteome is challenging, but is of crucial importance to cell function. Defects in mitochondrial proteostasis lead to proteotoxic insults and eventually cell death. Different quality control systems monitor the mitochondrial proteome. The cytosolic ubiquitin–proteasome system controls protein transport across the mitochondrial outer membrane and removes damaged or mislocalized proteins. Concomitantly, a number of mitochondrial chaperones and proteases govern protein folding and degrade damaged proteins inside mitochondria. The quality control factors also regulate processing and turnover of native proteins to control protein import, mitochondrial metabolism, signalling cascades, mitochondrial dynamics and lipid biogenesis, further ensuring proper function of mitochondria. Thus, mitochondrial protein quality control mechanisms are of pivotal importance to integrate mitochondria into the cellular environment.

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Fig. 1: Quality control mechanisms of mitochondrial protein biogenesis.
Fig. 2: Quality control at the protein entry gate of mitochondria.
Fig. 3: Stress response pathways on impaired mitochondrial protein import.
Fig. 4: Degradation of proteins at the OMM.
Fig. 5: Protein quality control in inner mitochondrial compartments.

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Acknowledgements

The authors thank F. den Brave for critical reading of the manuscript. This work was supported by funds from the Deutsche Forschungsgemeinschaft (SFB 1218 project ID 269925409 and BE 4679/2-2 to T.B. and HE 2803/9-1 and DIP MitoBalance to J.M.H.).

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Glossary

Alphaproteobacteria

A class of Proteobacteria, which is a major phylum of Gram-negative bacteria. Alphaproteobacteria are highly diverse, comprising intracellular pathogens and phototropic bacteria.

Iron–sulfur clusters

Cofactors of proteins involved in electron transport, enzymatic catalysis and regulatory mechanisms.

Membrane contact sites

Close contacts between membrane-bound cell organelles that tether two organelles and contain a subset of proteins to fulfil specific functions, such as lipid transport and Ca2+ trafficking.

Ubiquitin

A 76 amino acid polypeptide that is transferred onto proteins either to target them for proteasomal degradation or to regulate their activity.

E3 ubiquitin ligases

A large group of proteins that transfer activated ubiquitins to proteins.

ATPase associated with various cellular activities proteases

(AAA proteases). Multimeric proteases that contain a proteolytic chamber and an AAA ATPase domain.

Mitophagy

A selective autophagy pathway that involves the core machinery of autophagy to remove damaged mitochondria by lysosomal degradation.

SNARE proteins

A protein family that promotes fusion of vesicles with target membranes.

TOM complex

The translocase of the outer membrane. It forms the major entry gate for precursor proteins into mitochondria.

TIM23 complex

The presequence translocase of the inner mitochondrial membrane. It integrates precursor proteins with a cleavable presequence into the inner membrane or transports them into the matrix.

Mitochondrial processing peptidase

(MPP). Removes the cleavable presequence of precursor proteins that are imported via the TIM23 complex.

Nascent polypeptide-associated complex

(NAC). A heterodynamic complex that binds to translating ribosomes.

Ubiquilins

Cytosolic chaperones that bind hydrophobic regions of their substrates during protein targeting and deliver them for proteasomal degradation.

Tail-anchored proteins

Membrane proteins with a carboxy-terminal α-helical transmembrane anchor.

Cdc48

Like its human homologue p97 (also known as VCP), it is a multifunctional AAA protein in the cytosol that extracts proteins from cellular membranes and protein complexes for proteasomal degradation.

ER-associated degradation

A process that removes misfolded proteins from the endoplasmic reticulum (ER). Substrate proteins are ubiquitylated and subsequently extracted from the ER to deliver them for proteasomal degradation.

Msp1

An AAA ATPase that extracts proteins from the outer membrane for proteasomal degradation.

Integrated stress response

A general cellular stress response pathway that is induced by various different stress situations. It leads to reduced general protein biosynthesis, but increased production of some transcription factors.

OMA1

An inner membrane metalloproteinase which together with the i-AAA protease controls the proteolytic cleavage of mitochondrial dynamics regulator OPA1.

Retrotranslocation

Reverse protein transport from cell organelles into the cytosol.

Succinate dehydrogenase

Complex II of the respiratory chain, which oxidizes succinate to fumarate in the tricarboxylic acid cycle.

OPA1

GTPase that controls fusion of the inner membrane and modulates the formation of cristae.

Mitochondrial transcription factor A

(TFAM). Protein that binds to mitochondrial DNA to maintain its transcription and stability.

Aconitase

An iron–sulfur cluster-containing enzyme of the tricarboxylic acid cycle that converts citric acid to isocitric acid.

CODAS syndrome

A rare congenital disease that causes cerebral, ocular, dental, auricular and skeletal anomalies.

Perrault syndrome

A rare congenital syndrome with sensorineural deafness in males and females and associated ovarian dysgenesis in females.

Purkinje cells

Neurons in the cerebellum that produce the neurotransmitter γ-aminobutyric acid.

Ataxia

Perturbations of the nervous system that affect coordination of muscle movements.

Hereditary spastic paraplegia

Inherited diseases that are characterized by a progressive gait disorder.

Chronic ophthalmoplegia

Disease of the eye that is characterized by progressive impaired eye movement.

Amyloid precursor protein

A protein with unknown function that is proteolytically cleaved into amyloid-β peptides.

Amyloid-β peptide

Polypeptides that can aggregate into amyloid fibrils, which are a primary component of amyloid plaques in brains of people with Alzheimer disease.

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Song, J., Herrmann, J.M. & Becker, T. Quality control of the mitochondrial proteome. Nat Rev Mol Cell Biol 22, 54–70 (2021). https://doi.org/10.1038/s41580-020-00300-2

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