Mitochondrial Protein Quality Control: The Mechanisms Guarding Mitochondrial Health

Bohovych, Iryna; Chan, Sherine S.L.; Khalimonchuk, Oleh

doi:10.1089/ars.2014.6199

Cited by 81 publications

(65 citation statements)

References 203 publications

(254 reference statements)

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“…Mitochondrial degradation can occur at multiple scales, including removal of damaged molecules by proteases, lipases, and DNA degradation machinery (Bohovych et al 2015; Scheibye-Knudsen et al 2015); removal of more localized or minor damage by small mitochondria-derived vesicles (recently termed “micro-mitophagy”), and mitophagy (Lemasters 2014; Sugiura et al 2014). Of these, only mitophagy requires mitochondrial fission, as elongated mitochondrial are somewhat recalcitrant to mitophagy.…”

Section: Mitochondrial Dynamics: Fusion and Fission Transport Bimentioning

confidence: 99%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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Mitochondrial dynamics are regulated by two sets of opposed processes: mitochondrial fusion and fission, and mitochondrial biogenesis and degradation (including mitophagy), as well as processes such as intracellular transport. These processes maintain mitochondrial homeostasis, regulate mitochondrial form, volume and function, and are increasingly understood to be critical components of the cellular stress response. Mitochondrial dynamics vary based on developmental stage and age, cell type, environmental factors, and genetic background. Indeed, many mitochondrial homeostasis genes are human disease genes. Emerging evidence indicates that deficiencies in these genes often sensitize to environmental exposures, yet can also be protective under certain circumstances. Inhibition of mitochondrial dynamics also affects elimination of irreparable mitochondrial DNA (mtDNA) damage and transmission of mtDNA mutations. We briefly review the basic biology of mitodynamic processes with a focus on mitochondrial fusion and fission, discuss what is known and unknown regarding how these processes respond to chemical and other stressors, and review the literature on interactions between mitochondrial toxicity and genetic variation in mitochondrial fusion and fission genes. Finally, we suggest areas for future research, including elucidating the full range of mitodynamic responses from low to high-level exposures, and from acute to chronic exposures; detailed examination of the physiological consequences of mitodynamic alterations in different cell types; mechanism-based testing of mitotoxicant interactions with interindividual variability in mitodynamics processes; and incorporating other environmental variables that affect mitochondria, such as diet and exercise.

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Section: Mitochondrial Dynamics: Fusion and Fission Transport Bimentioning

confidence: 99%

Mitochondrial fusion, fission, and mitochondrial toxicity

2017

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“…Protein quality control is central to cellular function and survival in all living organisms 1 . Maintaining protein quality control relies on a complex network of ATP-dependent proteases that regulate protein homeostasis (or proteostasis) 2 . The membrane-anchored AAA+ protease FtsH is essential for growth in E. coli, and is evolutionarily conserved across all kingdoms of life 3 .…”

Section: Introductionmentioning

confidence: 99%

Unique structural features of the mitochondrial AAA+ protease AFG3L2 reveal the molecular basis for activity in health and disease

Puchades

Ding

Song

et al. 2019

Preprint

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Mitochondrial AAA+ quality control proteases regulate diverse aspects of mitochondrial biology through specialized protein degradation, but the underlying molecular mechanisms that define the diverse activities of these enzymes remain poorly defined. The mitochondrial AAA+ protease AFG3L2 is of particular interest, as genetic mutations localized throughout AFG3L2 are linked to diverse neurodegenerative disorders. However, a lack of structural data has limited our understanding of how mutations impact enzymatic activity. Here, we used cryo-EM to determine a substrate-bound structure of the catalytic core of human AFG3L2. This structure identifies multiple specialized structural features within AFG3L2 that integrate with conserved structural motifs required for hand-over-hand ATP-dependent substrate translocation to engage, unfold and degrade targeted proteins. Mapping disease-relevant AFG3L2 mutations onto our structure demonstrates that many of these mutations localize to these unique structural features of AFG3L2 and distinctly influence its activity and stability. Our results provide a molecular basis for neurological phenotypes associated with different AFG3L2 mutations, and establish a structural framework to understand how different members of the AAA+ superfamily achieve specialized, diverse biological functions.

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“…Thus, mechanisms for decreasing heteroplasmy at this bottleneck are important for reducing the transmission of mtDNA mutations and the incidence of mitochondrial disease. With aging, there is a decline in mitochondrial homeostasis (Bohovych et al 2015), and this may greatly contribute to the increased number of heteroplasmies transmitted to offspring, as shown by a positive correlation with maternal age (Rebolledo-Jaramillo et al 2014). …”

Section: Origins and Consequences Of Mtdna Instabilitymentioning

confidence: 99%

Inherited mitochondrial genomic instability and chemical exposures

Chan

2017

Toxicology

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There are approximately 1,500 proteins that are needed for mitochondrial structure and function, most of which are encoded in the nuclear genome (Calvo et al. 2006). Each mitochondrion has its own genome (mtDNA), which in humans encodes 13 polypeptides, 22 tRNAs and 2 rRNAs required for oxidative phosphorylation. The mitochondrial genome of humans and most vertebrates is approximately 16.5 kbp, double-stranded, circular, with few non-coding bases. Thus, maintaining mtDNA stability, that is, the ability of the cell to maintain adequate levels of mtDNA template for oxidative phosphorylation is essential and can be impacted by the level of mtDNA mutation currently within the cell or mitochondrion, but also from errors made during normal mtDNA replication, defects in mitochondrial quality control mechanisms, and exacerbated by exposures to exogenous and/or endogenous genotoxic agents. In this review, we expand on the origins and consequences of mtDNA instability, the current state of research regarding the mechanisms by which mtDNA instability can be overcome by cellular and chemical interventions, and the future of research and treatments for mtDNA instability.

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Mitochondrial Protein Quality Control: The Mechanisms Guarding Mitochondrial Health

Cited by 81 publications

References 203 publications

Mitochondrial fusion, fission, and mitochondrial toxicity

Mitochondrial fusion, fission, and mitochondrial toxicity

Unique structural features of the mitochondrial AAA+ protease AFG3L2 reveal the molecular basis for activity in health and disease

Inherited mitochondrial genomic instability and chemical exposures

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