A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

Lehmer, Carina; Schludi, Martin H.; Ransom, Linnea; Greiling, Johanna; Junghänel, Michaela; Exner, Nicole; Riemenschneider, Henrick; Zee, Julie van der; Broeckhoven, Christine Van; Weydt, Patrick; Heneka, Michael T.; Edbauer, Dieter

doi:10.15252/emmm.201708558

Cited by 43 publications

(47 citation statements)

References 38 publications

(66 reference statements)

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“…Only a mutant lacking a C-terminal CHCHD domain failed to rescue the C2C10H S81L -induced phenotype ( fig. S3D), which may reflect the failure of CHCHD10 ΔCHCHD mitochondrial localization, as previously reported (34).…”

Section: Chchd10 S59l -Induced Phenotypes Are Rescued By Wt and Mutansupporting

confidence: 81%

“…Our findings with CHCHD10 G58R and CHCHD10 G66V are more difficult to interpret because of their disparate results in Drosophila and HeLa cells. Although similar steady-state expression levels occurred in Drosophila and HeLa cells, CHCHD10 G58R and CHCHD10 G66V expression is considerably reduced when compared with that of CHCHD10 WT or CHCHD10 S59L (34).…”

Section: Discussionmentioning

confidence: 71%

“…We used a split GFP strategy because of possibly mislocalized C-terminal GFP-tagged CHCHD10 (34). The combination of GFP11-tagged CHCHD10 S59L with mitochondrial-localized GFP1-10 revealed that CHCHD10 S59L does not disrupt mitochondrial membrane potential, although it induced mitochondrial fragmentation ( fig.…”

Section: Pink1 Activation Does Not Disrupt Mitochondrial Membrane Potmentioning

confidence: 99%

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Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Baek

Choe

Dorn³

et al. 2019

Preprint

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†Authors contributed equally.One Sentence Summary: Inhibition of TDP-43 mitochondrial translocation or PINK1 kinase activity mitigates CHCHD10 S59L -mediated mitochondrial toxicity. AbstractMutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS-FTD). To elucidate how mutations in CHCHD10 induce disease, we generated a Drosophila melanogaster model of CHCHD10-mediated ALS-FTD. Expression of CHCHD10 S59L in Drosophila caused gain-offunction toxicity in eyes, motor neurons, and muscles, in addition to mitochondrial defects in flies and HeLa cells. TDP-43 and PINK1 formed two axes, driving the mutant-dependent phenotypes. CHCHD10 S59L expression increased TDP-43 insolubility and mitochondrial translocation. Blocking mitochondrial translocation with a peptide inhibitor reduced CHCHD10 S59L -mediated toxicity. PINK1 knockdown rescued CHCHD10 S59L -mediated phenotypes in Drosophila and HeLa cells. The two PINK1 substrates mitofusin and mitofilin were genetic modifiers of this phenotype. Mitofusin agonists reversed the CHCHD10 S59Linduced phenotypes in Drosophila and HeLa cells and increased ATP production in Drosophila expressing C9orf72 with expanded GGGGCC repeats. Two peptides inhibitors of PINK1 mitigated the mitochondrial defects introduced by CHCHD10 S59L expression. These findings indicate that TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways by CHCHD10 S59L generate dominant toxicity. Therefore, inhibiting PINK1 activity may provide a therapeutic strategy for CHCHD10-associated disease.

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Section: Chchd10 S59l -Induced Phenotypes Are Rescued By Wt and Mutansupporting

confidence: 81%

Section: Discussionmentioning

confidence: 71%

Section: Pink1 Activation Does Not Disrupt Mitochondrial Membrane Potmentioning

confidence: 99%

See 1 more Smart Citation

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Baek

Choe

Dorn³

et al. 2019

Preprint

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“…Analogously, other studies reported that the overexpression of mutant versions of mitochondrial proteins, such as NUBPL and FOXRED1, was able to reverse the pathological phenotype in patient cells (Tucker et al , ; Formosa et al , ). The stimulation of mitochondrial import of the pathogenic mutant CHCHD10 was recently proposed as a possible therapeutic strategy for amyotrophic lateral sclerosis (Lehmer et al , ). Our data suggest that the inhibition of excessive degradation by the proteasome can rescue mitochondrial function in diseases that are associated with the mislocalization and premature degradation of mitochondrial proteins.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

et al. 2019

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Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space ( IMS ) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein cytochrome c oxidase assembly factor 7 ( COA 7), or RES piratory chain Assembly 1 ( RESA 1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA 7 requires the mitochondrial IMS import and assembly ( MIA ) pathway for efficient accumulation in the IMS . We also found that pathogenic mutant versions of COA 7 are imported slower than the wild‐type protein, and mislocalized proteins are degraded in the cytosol by the proteasome. Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA 7 and complex IV activity in patient‐derived fibroblasts. We propose proteasome inhibition as a novel therapeutic approach for a broad range of mitochondrial pathologies associated with the decreased levels of mitochondrial proteins.

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“…Analogously, other studies reported that the overexpression of mutant versions of mitochondrial proteins, such as NUBPL and FOXRED1, was able to reverse the pathological phenotype in patient cells (Formosa et al, 2015;Tucker et al, 2012). The stimulation of mitochondrial import of the pathogenic mutant CHCHD10 was recently proposed as a possible therapeutic strategy for amyotrophic lateral sclerosis (Lehmer et al, 2018). Our data suggest that the inhibition of excessive degradation by the proteasome can rescue mitochondrial function in diseases that are associated with the mislocalization and premature degradation of mitochondrial proteins.…”

Section: Discussionmentioning

confidence: 89%

Inhibition of proteasomal degradation rescues a pathogenic variant of mitochondrial Respiratory chain assembly 1 factor

Mohanraj

Wasilewski

Benincá

et al. 2018

Preprint

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Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein, RESpiratory chain Assembly 1 (RESA1) factor, or cytochrome c oxidase assembly factor 7 (COA7) that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that RESA1 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS. We also found that pathogenic mutant versions of RESA1 are imported slower than the wild type protein, and mislocalized mutant proteins are degraded in the cytosol by proteasome machinery. Interestingly, proteasome inhibition rescued both the mitochondrial localization of mutant RESA1 and complex IV activity in patient-derived fibroblasts. We propose that proteasome inhibition is a novel therapeutic approach for a broad range of mitochondrial pathologies that are associated with the excessive degradation of mitochondrial proteins that is caused by genetic mutations or biogenesis defects.

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A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

Cited by 43 publications

References 38 publications

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

Inhibition of proteasomal degradation rescues a pathogenic variant of mitochondrial Respiratory chain assembly 1 factor

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A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

Cited by 43 publications

References 38 publications

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

Inhibition of proteasomal degradation rescues a pathogenic variant of mitochondrial Respiratory chain assembly 1 factor

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Resources

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Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1