The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

Purandare, Neeraja; Somayajulu, Mallika; Hüttemann, Maik; Grossman, Lawrence I.; Aras, Siddhesh

doi:10.1074/jbc.ra117.001073

Cited by 49 publications

(58 citation statements)

References 42 publications

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“…Like mitofilin and L‐OPA1, we observed no detectable differences in the overall levels of Mfn2, Drp1, or CHCHD2 proteins. However, we cannot rule out the possibility that different complexes of these proteins are altered by CHCHD10 mutations, particularly CHCHD2, which has been reported to form a complex with CHCHD10 44,50‐52 . Interestingly, a recent study using a Drosophila model reported that the WT version of Drosophila CHCHD2 increases OPA1 levels, while CHCHD2 mutations decrease OPA1 through as yet unknown mechanism 53 …”

Section: Discussionmentioning

confidence: 93%

CHCHD10‐regulated OPA1‐mitofilin complex mediates TDP‐43‐induced mitochondrial phenotypes associated with frontotemporal dementia

et al. 2020

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Mutations in CHCHD10, a gene coding for a mitochondrial protein, are implicated in ALS‐FTD spectrum disorders, which are pathologically characterized by transactive response DNA binding protein 43 kDa (TDP‐43) accumulation. While both TDP‐43 and CHCHD10 mutations drive mitochondrial pathogenesis, mechanisms underlying such phenotypes are unclear. Moreover, despite the disruption of the mitochondrial mitofilin protein complex at cristae junctions in patient fibroblasts bearing the CHCHD10S59L mutation, the role of CHCHD10 variants in mitofilin‐associated protein complexes in brain has not been examined. Here, we utilized novel CHCHD10 transgenic mouse variants (WT, R15L, & S59L), TDP‐43 transgenic mice, FTLD‐TDP patient brains, and transfected cells to assess the interplay between CHCHD10 and TDP‐43 on mitochondrial phenotypes. We show that CHCHD10 mutations disrupt mitochondrial OPA1‐mitofilin complexes in brain, associated with impaired mitochondrial fusion and respiration. Likewise, CHCHD10 levels and OPA1‐mitofilin complexes are significantly reduced in brains of FTLD‐TDP patients and TDP‐43 transgenic mice. In cultured cells, CHCHD10 knockdown results in OPA1‐mitofilin complex disassembly, while TDP‐43 overexpression also reduces CHCHD10, promotes OPA1‐mitofilin complex disassembly via CHCHD10, and impairs mitochondrial fusion and respiration, phenotypes that are rescued by wild type (WT) CHCHD10. These results indicate that disruption of CHCHD10‐regulated OPA1‐mitofilin complex contributes to mitochondrial abnormalities in FTLD‐TDP and suggest that CHCHD10 restoration could ameliorate mitochondrial dysfunction in FTLD‐TDP.

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Section: Discussionmentioning

confidence: 93%

CHCHD10‐regulated OPA1‐mitofilin complex mediates TDP‐43‐induced mitochondrial phenotypes associated with frontotemporal dementia

et al. 2020

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“…1,6 CHCHD10 forms part of the multiprotein complex MICOS, which plays a vital role in the formation and maintenance of cristae structure. 7 A recent study 8 demonstrated that CHCHD10 is a regulator of mitochondrial respiration and can contribute to transcriptional repression of oxygen-responsive element containing genes, and some genetic CHCHD10 variants (G66V and P80L) are impaired in these activities.…”

Section: Discussionmentioning

confidence: 99%

Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis

et al. 2020

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ObjectiveTo present the postmortem neuropathologic report of a patient with a CHCHD10 mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.MethodsA 54-year-old man without significant medical history or family history presented with arm weakness, slowly progressed over 19 years to meet the El Escorial criteria for clinically probable ALS with bulbar and respiratory involvement, and was found to have a CHCHD10 p.R15L mutation. Postmortem neuropathologic examination took place including immunohistochemical staining with CHCHD10, and double immunofluorescence combining CHCHD10 with TDP43 and neurofilament was performed and the results were compared with normal controls and sporadic ALS cases.ResultsPostmortem examination of the CHCHD10 mutation carrier showed severe loss of hypoglossal and anterior horn motor neurons, mild corticospinal tract degeneration, and a relative lack of TDP43 immunopathology. CHCHD10 immunohistochemistry for the 3 controls and the 5 sporadic ALS cases showed strong neuronal cytoplasmic and axonal labeling, with the CHCHD10 mutation carrier also having numerous CHCHD10 aggregates within their anterior horns. These aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model. The CHCHD10 aggregates did not colocalize with TDP43 and were predominantly extracellular on double immunofluorescence labeling with neurofilament.ConclusionsThe neuropathology of CHCHD10 mutated ALS includes predominantly lower motor neuron degeneration, absent TDP43 immunopathology, and aggregates of predominantly extracellular CHCHD10, which do not contain TDP43.

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“…CHCHD10 is strongly expressed in muscle and heart and in specific cell types of the central nervous system (CNS), including dopaminergic neurons of the midbrain and motor neurons in the spinal cord [1,4,15]. Although the normal roles of CHCHD10 and CHCHD2 remain unknown, both proteins have short half-lives [4,30,35], suggesting that they may have signaling or transport, rather than structural, functions.…”

Section: Introductionmentioning

confidence: 99%

ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response

et al. 2019

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Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10 S55L mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10 S55L mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR)

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The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

Cited by 49 publications

References 42 publications

CHCHD10‐regulated OPA1‐mitofilin complex mediates TDP‐43‐induced mitochondrial phenotypes associated with frontotemporal dementia

CHCHD10‐regulated OPA1‐mitofilin complex mediates TDP‐43‐induced mitochondrial phenotypes associated with frontotemporal dementia

Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis

ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response

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