The importance of TP53/p53 in regulating the mitophagy-lysosomal machinery in muscle following disuse

Abstract

Since being discovered in the late 1990s, TP53/TRP53/p53 has been a focal point of research, lauded for its role as a tumor-suppressor protein. Considerable attention has also been devoted to understanding how TP53 regulates metabolic programming of the cell, focusing on the control of skeletal muscle mitochondria. This research has implications that extend not only to muscle fitness, but also to healthy aging, and the prevention of metabolic disease. Previous work from our lab and others has indicated that TP53 is involved in mediating mitochondrial quality control mechanisms in muscle, such as mitochondrial biogenesis, and clearance via mitophagy. However, the degree to which TP53 is required to regulate these mitochondrial adaptations, at this point, has remained controversial, and has not yet been studied under conditions that promote accelerated mitochondrial dysfunction, such as with prolonged muscle disuse. We set out to determine the necessity of TP53 to maintain mitochondrial content and function in muscle, both basally as well as following acute and chronic muscle disuse. To accomplish this, we made use of RNA-sequencing, among other biochemical assessments of mitochondrial content and function, whereby we assessed the effect of TP53 ablation in muscle on >20,000 genes. We provide convincing evidence suggesting that TP53 has a minor role in the basal maintenance of mitochondria in muscle; however, under the stress of chronic disuse, the absence of TP53 contributes to exacerbated declines in mitochondrial function brought about by defects in mitochondrial quality control (MQC) pathways, particularly within the mitophagy-lysosomal machinery.