C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly

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

“…A recent work showed that C9orf72, encoded by the most frequently mutated gene in ALS and FTD, is imported in the inter mitochondrial space. C9orf72 recruits the PHB complex to stabilize TIMMDC1, an assembly factor of mitochondrial complex I the function of which is impaired in ALS/FTD patient-derived neurons bearing C9orf72 mutations (Wang et al , 2021). However, to our knowledge, a direct involvement of the instability of the PHB complex has never been reported in vivo neither in ALS/FTD nor in other neurodegenerative diseases.…”

C9ORF72: What It Is, What It Does, and Why It Matters

“…C9ORF72 was detected in synaptosome preparations from mouse brains and co-localized with synaptic markers in mouse brain tissues and human induced pluripotent stem cell (iPSC)-derived motor neurons ( Atkinson et al, 2015 ; Ferguson et al, 2016 ; Frick et al, 2018 ), supporting a role for C9ORF72 at the synapses. Further studies using tagged C9ORF72, transfected or CRISPR modified, or immunocytochemical detection of endogenous C9ORF72 in cell lines or human iPSC-derived neurons have revealed the co-localization of C9ORF72 with various organelles: the Golgi apparatus ( Aoki et al, 2017 ), stress granules ( Maharjan et al, 2017 ; Chitiprolu et al, 2018 ), mitochondria ( Wang et al, 2021 ), and, most of all, compartments of the endolysosomal pathway ( Farg et al, 2014 ; Sellier et al, 2016 ; Amick et al, 2016 ; Frick et al, 2018 ; Shi et al, 2018 ; Wang et al, 2020 ). Recently, an extensive study comparing the 14 commercially available antibodies revealed that many of these antibodies that were used in previous studies fail to properly detect C9ORF72 ( Laflamme et al, 2019 ).…”

“…Actin filament assembly and disassembly are necessary for axonal maintenance and synaptic strength ( Flynn et al, 2012 ; Huang et al, 2013 ); thus, the alteration of this dynamic may account for the axonal phenotype observed in C9ORF72-depleted mouse motor neurons and iPSC-derived motor neurons from C9-ALS patients ( Sivadasan et al, 2016 ). Neuronal activity and synaptic function also depend on the energy supply provided by mitochondrial oxidative phosphorylation (OXPHOS) complexes ( Rangaraju et al, 2019 ), and C9ORF72 was very recently shown to regulate the activity of these complexes ( Wang et al, 2021 ). By interacting with AIFM1, C9ORF72 is imported to the mitochondrial intermembrane space, where it interacts with TIMMDC1 and the prohibitin (PHB) complex to stabilize OXPHOS complex I (CI) subunits to allow their assembly.…”

“…By interacting with AIFM1, C9ORF72 is imported to the mitochondrial intermembrane space, where it interacts with TIMMDC1 and the prohibitin (PHB) complex to stabilize OXPHOS complex I (CI) subunits to allow their assembly. In the absence of C9ORF72 as well as in iPSC-derived motor neurons from C9-ALS patients, the level of mature CI and CI activity were reduced ( Wang et al, 2021 ).…”

Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration

“…A novel CHCHD10 variant, Q108P, discovered in a patient with rapidly progressing ALS, has been shown to almost completely abolish its import, resulting in reduced mitochondrial respiratory capacity, an effect that is rescued by overexpression of CHCHD4 ( Table 2 ) [ 335 ]. Interestingly, the C9orf72 protein, which is often mutated in cases of ALS and frontotemporal dementia, has recently been shown to be an IMM protein vital for the assembly and stabilisation of CI, and its translocation occurs via the MIA pathway [ 336 ]. These studies demonstrate the importance of mitochondrial protein import and proper respiratory function in the prevention of motor neuron diseases such as ALS, highlighting import pathways as interesting potential targets for treatment.…”