Peroxisome loss leads to increased mitochondrial biogenesis and reduced autophagy to preserve mitochondrial function

Abstract

Abstract Peroxisomes are essential for mitochondrial health. However, the mechanisms underlying the relationship between these two organelles in hepatic metabolism remains unclear. To address this, we developed a conditional hepatocyte specific Pex16 deficient mouse (Pex16 KO) and subjected these animals to a low protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and a reduction in autophagy flux but with preserved capacity for respiration and ATP production. Metabolic stress induced by low protein feeding did lead to mitochondrial dysfunction in Pex16 KO mice and impaired the ability to upregulate its biogenesis. Activation of PPARα partially corrected the mitochondrial disturbances caused by low protein feeding, independent of the presence of peroxisomes. This study shows that peroxisome loss in hepatocytes affects mitochondrial biogenesis and autophagy, thereby preserving mitochondrial function and underscore the relation between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.