Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function

Abstract

Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.

Mechanisms of Modulation of Mitochondrial Architecture

“…Mitochondrial–peroxisome interaction plays a relevant role in fatty acid metabolism and in cellular redox homeostasis; a coordinate function of these organelles is required to sustain mitochondrial activity. Studies have shown that peroxisomal protein (PEX5 or PEX16) ablation in mice livers led to mitochondrial dysfunction and fragmentation [ 30 , 31 ]. Moreover, PEX16 knockout mice showed that peroxisomes are required to sustain mitochondrial homeostasis upon metabolic stress induced by a high fat diet [ 31 ].…”

“…Studies have shown that peroxisomal protein (PEX5 or PEX16) ablation in mice livers led to mitochondrial dysfunction and fragmentation [ 30 , 31 ]. Moreover, PEX16 knockout mice showed that peroxisomes are required to sustain mitochondrial homeostasis upon metabolic stress induced by a high fat diet [ 31 ]. Two proteins involved in mitochondria–peroxisome tethering have been identified, enoyl-CoA-δ isomerase 2 (ECI2) and the lipid transport protein VPS13D [ 32 , 33 ].…”