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

Tian Liu, Jung A.A. Woo, Mohammed Zaheen Bukhari, Patrick LePochat, Ann Chacko, Maj Linda B. Selenica, Yan Yan, Peter Kotsiviras, Sara Cazzaro Buosi, Xingyu Zhao, David E. Kang

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish
Pages (from-to)8493-8509
Number of pages17
JournalFASEB Journal
Issue number6
StatePublished - Jun 1 2020

Bibliographical note

Funding Information:
We thank Dr. Alexander M. van der Bliek (University of California, Los Angeles, CA) for providing OPA1‐myc construct, Drs. Allan Levey and Gearing (Emory University) for providing postmortem human brain tissues, Dr. David Borchelt (University of Florida) for providing the MoPrP.Xho transgenic construct. This work was supported in part by grants from the NIH (1RF1AG053060‐01A1, DEK; 5R01NS073899, DEK), VA (1 I01 BX002478‐01A1, DEK), and Florida department of Health (8AZ29, DEK & JAW).

Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology


  • CHCHD10
  • OPA1
  • TDP-43
  • frontotemporal dementia
  • mitofilin

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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