Consequences of inner mitochondrial membrane protein misfolding

Coyne, Liam P.; Chen, Xin Jie

doi:10.1016/j.mito.2019.06.001

Cited by 20 publications

(16 citation statements)

References 86 publications

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“…Such stress responses are implicated in several pathological conditions like aging, muscle degeneration, and neurodegeneration (Lin and Beal, 2006, Tatsuta and Langer, 2008, Zhu et al, 2021). In addition, the accumulation of these hydrophobic proteins in the cytosol further dampens the import of other essential cytosolic and mitochondrial proteins (Coyne and Chen, 2019). Also, overloading of the carrier proteins in humans induces cytosolic aggresomes and activates apoptotic pathways (Liu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Functional crosstalk between the carrier translocase machinery and YME1 complex maintains mitochondrial proteostasis and integrity

Kumar

D’Silva

2022

Preprint

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The TIM22 pathway cargos are essential for sustaining mitochondrial proteostasis as an excess of these proteins leads to proteostatic stress and cell death. Yme1 is an inner membrane metalloprotease that regulates proteostasis with its chaperone-like and proteolytic activities. Although the mitochondrial translocase and protease machinery are critical for organelle health, the functional link between these complexes remains unexplored. The present study unravels a novel genetic connection between the TIM22 complex and YME1 machinery in maintaining mitochondrial proteostasis and quality control. Our genetic analyses indicate that impairment in the TIM22 complex rescues the respiratory growth defects of cells without Yme1. We further demonstrate that Yme1 is essential for the stability of the TIM22 complex and regulating the proteostasis of the TIM22 pathway substrates. Moreover, impairment in the TIM22 complex suppressed the mitochondrial structural and functional defects of Yme1 devoid cells. Notably, the functional dependence between the TIM22 and YME1 complexes remains functionally conserved from yeast to humans. Our findings suggest that excessive levels of the TIM22 pathway substrates could be one of the reasons for the respiratory growth defects of cells lacking Yme1 and compromising the TIM22 complex compensate for the imbalance in mitochondrial proteostasis caused by loss of Yme1.

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Section: Discussionmentioning

confidence: 99%

Functional crosstalk between the carrier translocase machinery and YME1 complex maintains mitochondrial proteostasis and integrity

Kumar

D’Silva

2022

Preprint

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“…Previous studies reported that MIC60 was altered and misfolded under several different pathological conditions [ 29 , 30 ]. To maintain homeostasis in cells, misfolded proteins may be refolded to normal structure with the help of molecular chaperones, or degraded through a ubiquitin-proteasome system or lysosome [ 31 ]. TRAP1 was reported to regulate mitochondrial proteins quality control and ubiquitination [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

TRAP1 inhibits MIC60 ubiquitination to mitigate the injury of cardiomyocytes and protect mitochondria in extracellular acidosis

Zhang

Luo

et al. 2021

Cell Death Discov.

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Extracellular acidosis-induced mitochondrial damage of cardiomyocytes leads to cardiac dysfunction, but no detailed mechanism or efficient therapeutic target has been reported. Here we found that the protein levels of MIC60 were decreased in H9C2 cells and heart tissues in extracellular acidosis, which caused mitochondrial damage and cardiac dysfunction. Overexpression of MIC60 maintains H9C2 cells viability, increases ATP production and mitochondrial membrane potential, mitigates the disruptions of mitochondrial structure and cardiac injury. Mechanistically, extracellular acidosis excessively promoted MIC60 ubiquitin-dependent degradation. TRAP1 mitigated acidosis-induced mitochondrial impairments and cardiac injury by directly interacting with MIC60 to decrease its ubiquitin-dependent degradation in extracellular acidosis.

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“…Accumulation of mtDNA mutations may be a consequence of the loss of mtDNA replication precursors following membrane permeabilization [ 42 ]. More recently, it was proposed that misfolding and propensity to form large aggregates by Aac2 mutant could generate stress on the membrane, affecting mitochondrial biogenesis, particularly causing severe damage to the electron transport chain assembly and mtDNA integrity [ 45 , 251 , 252 ]. Nevertheless, the experiments performed so far are not yet conclusive, and none of these hypotheses seem to be totally clarifyied for now.…”

Section: Genes Studied In Yeastmentioning

confidence: 99%

Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability

Gilea

Berti

Magistrati

et al. 2021

Genes

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Mitochondrial DNA (mtDNA) maintenance is critical for oxidative phosphorylation (OXPHOS) since some subunits of the respiratory chain complexes are mitochondrially encoded. Pathological mutations in nuclear genes involved in the mtDNA metabolism may result in a quantitative decrease in mtDNA levels, referred to as mtDNA depletion, or in qualitative defects in mtDNA, especially in multiple deletions. Since, in the last decade, most of the novel mutations have been identified through whole-exome sequencing, it is crucial to confirm the pathogenicity by functional analysis in the appropriate model systems. Among these, the yeast Saccharomyces cerevisiae has proved to be a good model for studying mutations associated with mtDNA instability. This review focuses on the use of yeast for evaluating the pathogenicity of mutations in six genes, MPV17/SYM1, MRM2/MRM2, OPA1/MGM1, POLG/MIP1, RRM2B/RNR2, and SLC25A4/AAC2, all associated with mtDNA depletion or multiple deletions. We highlight the techniques used to construct a specific model and to measure the mtDNA instability as well as the main results obtained. We then report the contribution that yeast has given in understanding the pathogenic mechanisms of the mutant variants, in finding the genetic suppressors of the mitochondrial defects and in the discovery of molecules able to improve the mtDNA stability.

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Consequences of inner mitochondrial membrane protein misfolding

Cited by 20 publications

References 86 publications

Functional crosstalk between the carrier translocase machinery and YME1 complex maintains mitochondrial proteostasis and integrity

Functional crosstalk between the carrier translocase machinery and YME1 complex maintains mitochondrial proteostasis and integrity

TRAP1 inhibits MIC60 ubiquitination to mitigate the injury of cardiomyocytes and protect mitochondria in extracellular acidosis

Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability

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