Chchd10, encoding a coiled-coil-helix-coiled-coil-helix-domain containing protein, is a nuclear-encoded mitochondrial protein involved in cristae organization [6,7]. It is also associated with mitochondrial metabolic processes, and its homolog is CHCHD2 [8,9]. CHCHD2 and CHCHD10 may form heterodimers or homodimers within mitochondria [9]. Mutations in Chchd10 are linked to a spectrum of diseases including mitochondrial myopathy, cardiomyopathy, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) [1,3,4,5].

Chchd10S59L/+ knock-in mice phenotypically replicate disorders seen in patients, such as myopathy with mtDNA instability, cardiomyopathy, and typical ALS features like protein aggregation, neuromuscular junction degeneration, and spinal motor neuron loss. They also show impaired learning and memory, reduced long-term potentiation, protein aggregates, activation of the integrated stress response, and neuroinflammation in the hippocampus, validating them as a relevant FTD model [1]. Chchd10 G58R or S59L knock-in mice have higher mtDNA deletion levels in some tissues, with the deletion burden increasing with age. The spinal cord is less prone to mtDNA deletions, and Chchd10 mutations lead to a novel set of deletions with shorter direct repeats flanking the breakpoints [2]. Chchd10P80L knock-in zebrafish display a mild ALS-like phenotype with motor impairment, reduced survival, abnormal neuromuscular junctions, and transcriptional changes related to neuroinflammation, apoptosis, amino acid metabolism, and mt-DNA inflammatory response [5]. Adipocyte-specific Chchd10 knockout (Chchd10-AKO) mice have impaired UCP1-dependent thermogenesis and energy expenditure in the fasting state due to disrupted lipolysis, while Chchd10 overexpression activates thermogenic adipocytes [6]. Chchd10 knockout (Chchd10KO) mice have normal skeletal muscle and adipose tissue development but show blunted response to acute cold and attenuated cold-induced browning of white adipose tissue [7].

In conclusion, Chchd10 is crucial for maintaining mitochondrial function, especially in cristae organization. Model-based research, especially through KO/knock-in mouse models, has revealed its significant roles in various biological processes and disease conditions. These models contribute to understanding the pathogenesis of diseases like ALS, FTD, and metabolic disorders associated with Chchd10 mutations, potentially paving the way for new therapeutic strategies.