CHCHD10-regulated OPA1-mitofilin complex mediates TDP-43-induced mitochondrial phenotypes associated with frontotemporal dementia
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, me...
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Published in | The FASEB journal Vol. 34; no. 6; p. 8493 |
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Format | Journal Article |
Language | English |
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01.06.2020
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Abstract | 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 CHCHD10
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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AbstractList | 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 CHCHD10
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. |
Author | Chacko, Ann Kotsiviras, Peter Bukhari, Mohammed Zaheen Buosi, Sara Cazzaro Selenica, Maj-Linda B Yan, Yan Liu, Tian LePochat, Patrick Zhao, Xingyu Kang, David E Woo, Jung-A A |
Author_xml | – sequence: 1 givenname: Tian surname: Liu fullname: Liu, Tian organization: Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 2 givenname: Jung-A A surname: Woo fullname: Woo, Jung-A A organization: Department of Molecular Pharmacology and Physiology, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 3 givenname: Mohammed Zaheen surname: Bukhari fullname: Bukhari, Mohammed Zaheen organization: Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 4 givenname: Patrick surname: LePochat fullname: LePochat, Patrick organization: Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 5 givenname: Ann surname: Chacko fullname: Chacko, Ann organization: Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 6 givenname: Maj-Linda B surname: Selenica fullname: Selenica, Maj-Linda B organization: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA – sequence: 7 givenname: Yan surname: Yan fullname: Yan, Yan organization: Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 8 givenname: Peter surname: Kotsiviras fullname: Kotsiviras, Peter organization: Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 9 givenname: Sara Cazzaro surname: Buosi fullname: Buosi, Sara Cazzaro organization: Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 10 givenname: Xingyu surname: Zhao fullname: Zhao, Xingyu organization: Department of Molecular of Medicine, USF Health Morsani College of Medicine, Tampa, FL, USA – sequence: 11 givenname: David E surname: Kang fullname: Kang, David E organization: James A. Haley Veterans Administration Hospital, Tampa, FL, USA |
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Keywords | CHCHD10 frontotemporal dementia OPA1 mitofilin TDP-43 |
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SubjectTerms | Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism Animals Cell Line Cell Line, Tumor DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Frontotemporal Dementia - genetics Frontotemporal Dementia - metabolism GTP Phosphohydrolases - genetics GTP Phosphohydrolases - metabolism HEK293 Cells HeLa Cells Humans Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria - genetics Mitochondria - metabolism Mitochondrial Dynamics - genetics Mitochondrial Dynamics - physiology Mitochondrial Membranes - metabolism Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Muscle Proteins - genetics Muscle Proteins - metabolism Mutation - genetics NIH 3T3 Cells Phenotype |
Title | CHCHD10-regulated OPA1-mitofilin complex mediates TDP-43-induced mitochondrial phenotypes associated with frontotemporal dementia |
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