MITOCHONDRIAL PROTEIN AGGREGATION AS A DRIVER OF ALS: SLP2 AND PROHIBITIN PATHOLOGY

Neurodegenerative diseases are increasingly recognized as disorders of mitochondrial dysfunction and impaired protein homeostasis. In amyotrophic lateral sclerosis (ALS) and ALS/frontotemporal dementia (ALS/FTD), how mitochondrial proteostasis failure contributes to selective motor neuron degeneration remains poorly understood. Here, we identify the mitochondrial Stomatin-Like Protein 2 (SLP2)/Prohibitin (PHB) complex as a critical regulator of mitochondrial protein homeostasis in ALS.
We demonstrate that CHCHD10, an ALS/FTD-linked mitochondrial protein, interacts with SLP2 and is required for PHB complex stability at the inner mitochondrial membrane. In patient fibroblasts and Chchd10^S59L/+ mice, the disease-associated CHCHD10 mutation induces SLP2/PHB aggregation and destabilization of the PHB complex. This proteostatic imbalance activates the OMA1-OPA1 stress pathway, leading to mitochondrial fragmentation, disorganization of cristae architecture, impairment of the mitochondrial contact site and cristae organizing system (MICOS), and progressive degeneration of spinal motor neurons and hippocampal neurons (Genin EC et al., PMID:35656794).
Importantly, SLP2/PHB aggregation is not restricted to CHCHD10-associated ALS. We identify similar aggregates in Fus^ΔNLS mouse models and in post-mortem spinal cords from ALS and ALS/FTD patients, including cases with C9ORF72 mutations. The age-dependent accumulation and selective occurrence of these aggregates suggest subtype-specific vulnerabilities of mitochondrial protein homeostasis (Genin EC et al., PMID:41303337).
Together, our findings position SLP2/PHB complex destabilization as a convergent mitochondrial proteostasis defect driving neurodegeneration in ALS, highlighting mitochondrial quality control as a promising therapeutic target.