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

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 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.

Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology

“…Given the limitations of the technology in that we could not control levels of transgene expression with exquisite precision, we proceeded with the best available lines. A recent report describes the development of a transgenic mouse model expressing FLAG-tagged CHCHD10 under the control of the CNS-enriched Prp promoter ( Liu et al., 2020a ). FLAG-tagged CHCHD10-R15L transgenic mice display one-half the transgene expression level of the FLAG-tagged CHCHD10-WT control mice, again highlighting the inherent difficulties of obtaining transgenic mice with comparable transgene expression levels.…”

SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10S59L-related disease

“…Mutations in CHCHD10 have been found to be responsible for a large clinical spectrum including cardiomyopathy, ALS and/or FTD (Bannwarth et al , 2014; Liu et al , 2020; Johnson et al , 2014; Müller et al , 2014). It has been shown that CHCHD10 forms large aggregates with the paralog CHCHD2 protein in the affected tissues and it is very likely that CHCHD10/CHCHD2 aggregation is involved in the pathological process (Anderson et al , 2019; Huang et al , 2018).…”

“…SLP2 and the PHB complex are thus necessary to control the activity of OMA1 and the processing of OPA1. CHCHD2 variants, involved in Parkinson’s disease (PD), and CHCHD10 mutations lead to OMA1 activation when overexpressed in human cells (Liu et al , 2020). Here, we show that CHCHD10 is required with SLP2 for the maintenance of the PHB complex and that, in our models, OMA1 activation is triggered by the destabilization of this complex.…”

“…CHCHD10 S59L/+ cells CHCHD10 physically interacts with Mitofilin/MIC60, a key component of the MICOS complex (Liu et al, 2020;Genin et al, 2016;Pfanner et al, 2014) that is destabilized in CHCHD10 S59L/+ fibroblasts (Genin et al, 2018). Mitofilin also interacts with OPA1, and together, they control cristae junction number and stability (Glytsou et al, 2016;Barrera et al, 2016).…”

“…In both families, the transmission of the disease was autosomal dominant. Mutations in CHCHD10 were then associated with other clinical presentations, including early-onset mitochondrial myopathies (Ajroud-Driss et al , 2015) and cardiomyopathies (Salmon et al , 1971; Liu et al , 2020). The CHCHD10 gene was also involved in neurodegenerative disorders such as ALS (Johnson et al , 2014; Müller et al , 2014), FTD (Sirkis et al , 2019), late-onset spinal motor neuropathy (SMAJ) (Penttilä et al , 2015) and Charcot-Marie-Tooth disease type 2 (CMT2) (Auranen et al , 2015).…”