Abstract:The mitochondrion is a highly dynamic organelle that is critical for energy production and numerous metabolic processes. Drosophila Chchd2, a homolog of the human disease-related genes CHCHD2 and CHCHD10, encodes a mitochondrial protein. In this study, we found that loss of Chchd2 in flies resulted in progressive degeneration of photoreceptor cells and reduced muscle integrity. In the flight muscles of adult Chchd2 mutants, some mitochondria exhibited curling cristae and a reduced number of cristae compared to… Show more
“…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 …”
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.
“…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 …”
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.
“…Consistent with its mitochondrial and nuclear functions, the CHCHD2 hub interactome includes the mitochondrial protein C1qBP and the oncogenic transcription factor YBX1, as identified by unbiased affinity purification mass spectrometry (Wei et al, 2015). While other studies have independently validated the functional interaction of CHCHD2 with C1qBP (Seo et al, 2010;Liu W. et al, 2020), the functional consequences of CHCHD2-YBX1 interaction are unknown.…”
Section: Regulation Of Cell Migration and Differentiationmentioning
confidence: 99%
“…Coiled-coil-helix-coiled-coil-helix domain containing 2 is thought to be involved in the maintenance of mitochondrial cristae structure via its interaction with OPA1, a protein that mediates mitochondrial inner membrane fusion in response to mitochondrial stress (Liu W. et al, 2020;Liu Y.T. et al, 2020), and its interaction with MICS1, an inner membrane protein that regulates mitochondrial morphology and cytochrome c release (Meng et al, 2017;Lee et al, 2018).…”
Section: Regulation Of Mitochondrial Structure and Apoptosismentioning
Rare mutations in the mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) are associated with Parkinson’s disease (PD) and other Lewy body disorders. CHCHD2 is a bi-organellar mediator of oxidative phosphorylation, playing crucial roles in regulating electron flow in the mitochondrial electron transport chain and acting as a nuclear transcription factor for a cytochrome c oxidase subunit (COX4I2) and itself in response to hypoxic stress. CHCHD2 also regulates cell migration and differentiation, mitochondrial cristae structure, and apoptosis. In this review, we summarize the known disease-associated mutations of CHCHD2 in Asian and Caucasian populations, the physiological functions of CHCHD2, how CHCHD2 mutations contribute to α-synuclein pathology, and current animal models of CHCHD2. Further, we discuss the necessity of continued investigation into the divergent functions of CHCHD2 and CHCHD10 to determine how mutations in these similar mitochondrial proteins contribute to different neurodegenerative diseases.
“…CHCHD2 recently gained attention as mutations in this gene have been associated with neurodegenerative diseases, including Parkinson's Diseases ( 52 ). It was proposed that CHCHD2 competes with OPA1, a dynamin-like GTPase that regulates mitochondrial fusion and cristae structure, for the binding to C1QBP/P32, a previously identified CLPX interactor ( 53 , 54 ). Fig.…”
The mammalian mitochondrial proteome consists of more than 1100 annotated proteins and their proteostasis is regulated by only a few ATP-dependent protease complexes. Technical advances in protein mass spectrometry allowed for detailed description of the mitoproteome from different species and tissues and their changes under specific conditions. However, protease-substrate relations within mitochondria are still poorly understood. Here, we combined Terminal Amine Isotope Labeling of Substrates (TAILS) N termini profiling of heart mitochondria proteomes isolated from wild type and Clpp-/- mice with a classical substrate-trapping screen using FLAG-tagged proteolytically active and inactive CLPP variants to identify new ClpXP substrates in mammalian mitochondria. Using TAILS, we identified N termini of more than 200 mitochondrial proteins. Expected N termini confirmed sequence determinants for mitochondrial targeting signal (MTS) cleavage and subsequent N-terminal processing after import, but the majority were protease-generated neo-N termini mapping to positions within the proteins. Quantitative comparison revealed widespread changes in protein processing patterns, including both strong increases or decreases in the abundance of specific neo-N termini, as well as an overall increase in the abundance of protease-generated neo-N termini in CLPP-deficient mitochondria that indicated altered mitochondrial proteostasis. Based on the combination of altered processing patterns, protein accumulation and stabilization in CLPP-deficient mice and interaction with CLPP, we identified OAT, HSPA9 and POLDIP2 and as novel bona fide ClpXP substrates. Finally, we propose that ClpXP participates in the cooperative degradation of UQCRC1. Together, our data provide the first landscape of the heart mitochondrial N terminome and give further insights into regulatory and assisted proteolysis mediated by ClpXP.
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