Mitochondria, essential in eukaryotic cells for 1.5 billion years, support over 1,000 key metabolic reactions. Disruptions in the mitochondrial proteome can harm cellular health, contributing to aging and diseases like heart failure, diabetes, and cancer. Mitochondrial processing peptidases are crucial for maintaining the mitochondrial proteome, but their role in human diseases is not well understood due to a lack of suitable animal models.
In this study, we developed two animal models with selective deletion of the mitochondrial processing peptidase miPEP in either skeletal muscle or adipose tissue. miPEP plays a critical role in maturation of newly imported mitochondrial proteins and miPEP mutations lead to early mortality in humans. Skeletal muscle miPEP deletion accurately recapitulated the muscle pathology observed in humans with miPEP mutations, including atrophy, aberrant mitochondrial morphology, and deficiency of the respiratory complexes. These mice exhibited progressive muscle deterioration and loss of mitochondrial proteostasis leading to death around the age of 20 weeks. A multiomics profile of disease development showed that the activation of the integrated stress response (ISR) pathway occurs before the clinical symptoms appear, suggesting that this pathway plays a critical role in disease development.
Conversely, deleting miPEP in adipose tissue did not induce pathological consequences and resulted in a lean phenotype, improved insulin sensitivity, and resistance to diet-induced obesity. Further analysis revealed that adipose tissue miPEP deletion impaired brown adipocyte function, leading to dysfunctional adaptive thermogenesis and an inability to cope with cold-induced stress. Intriguingly, adipocyte specific miPEP deletion only partly activated ISR suggesting that the degree of ISR activation determines the physiological outcome associated with mitochondrial perturbations. We propose a model with the ISR at the centre of mitochondrial diseases.
These findings underscore the critical role of miPEP in metabolic homeostasis, offering insights into pathologies linked with ISR and offering novel therapeutic approaches for metabolic disorders linked to mitochondrial dysfunction.