Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features

Abstract

BackgroundMitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the ‘mitoskeleton’ due to its role in maintaining IMM architecture. APOO encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated.MethodsWe have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in APOO. Knockout models in Drosophila melanogaster and Saccharomyces cerevisiae were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.ResultsA likely pathogenic c.350T>C transition was found in APOO predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and D. melanogaster models.ConclusionThis is the first case of pathogenic mutation in APOO, causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.

MIC26 and MIC27 cooperate to regulate cardiolipin levels and the landscape of OXPHOS complexes

“…With a comprehensive functional analysis of cells after simultaneous deletion of MIC26 and MIC27 including a complexome approach, we revealed a novel cooperative function of these two proteins in determining the stability and integrity of the landscape of OXPHOS complexes. Further experiments are needed to provide mechanistic insights about how MIC26 and MIC27 affect OXPHOS complex biogenesis and cardiolipin levels and how this is linked to the pathophysiological role of these proteins in human diseases such as diabetic cardiomyopathy and mitochondrial myopathy (Beninca et al, 2020).…”

“…MIC10 and MIC60 are the core components of the MICOS complex because deletion of either of them causes virtually complete loss of CJs and cristae featuring as onion slices (Harner et al, 2011;Hoppins et al, 2011;von der Malsburg et al, 2011;Callegari et al, 2019;Kondadi et al, 2020). Mutations in bona fide subunits of MICOS, MIC60, MIC13, and MIC26 are found in human diseases such as Parkinson's (Tsai et al, 2018), mitochondrial encephalopathy with liver dysfunction (Guarani et al, 2016;Zeharia et al, 2016) and mitochondrial myopathy with lactic acidosis, cognitive impairment, and autistic features (Beninca et al, 2020), respectively.…”

Cristae Membrane Dynamics – A Paradigm Change

“…The subunits of the MICOS complex were functionally linked to maintenance of CJs, lipid trafficking, mitochondrial import, and mitochondrial DNA (mtDNA) maintenance [22,23]. Several MICOS subunits are associated with human diseases such as mitochondrial encephalopathy with liver disease, mitochondrial myopathy, neurodegeneration, cognitive impairment, and diabetes, among many others [1,[22][23][24][25][26][27][28][29]. Mic60 (alternative names mitofilin, HMP, IMMT, Fcj1) was the first subunit discovered, and its depletion led to loss of CJs and the formation of onion ring-like cristae in Saccharomyces cerevisiae (baker's yeast) and mammalian cell lines [21,30].…”

The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes

“…However, there was no evidence of mtDNA deletions or depletion in muscles and fibroblasts [ 242 , 243 , 244 ]. More recently, a mutation in APOO , encoding MIC26, has been reported to cause an X-linked disease associated with developmental delay, hypotonia, autistic spectrum disorder, gastrointestinal symptoms, lactic acidosis and abnormal carnitine profile [ 245 ]. The pathogenicity of the APOO variant was supported by work with fibroblasts and a fly model.…”