Peroxisomes govern mitochondrial dynamics and the mitochondrion dependent apoptotic pathway
Hideaki Tanaka, Yukiko Gotoh, Tomohiko Okazaki Graduate School of Pharmaceutical Sciences, The University of Tokyo
Recent studies have revealed that peroxisomes cooperate with mitochondria in the performance of cellular metabolic functions such as the oxidation of fatty acids and the maintenance of redox homeostasis. Whether peroxisomes play a role in mitochondrial fission or fusion or in mitochondrion-dependent caspase activation and apoptosis has remained unknown, however. We have now found that genetic ablation of either Pex3 or Pex5, peroxins essential for peroxisome biogenesis, resulted in fragmentation of mitochondria in mouse embryonic fibroblasts. Importantly, treatment with 4-phenylbutyric acid (4-PBA), an inducer of peroxisome proliferation, resulted in elongation of mitochondria in wild-type fibroblasts but not in Pex3 knockout cells. These results thus suggest that peroxisomes regulate mitochondrial dynamics in cells. We further found that peroxisome deficiency resulted in release of mitochondrial cytochrome c into the cytosol and increased the amounts of cleaved caspase-9 and caspase-3, although this caspase activation did not induce apoptosis. Peroxisomes thus appear to suppress mitochondrion-dependent (“sub-apoptotic”) caspase activation in the absence of apoptotic stimuli. We next examined whether peroxisomes regulate mitochondrion-dependent apoptosis induced by DNA damage. Treatment of fibroblasts with the DNA-damaging agent etoposide increased the proximity of peroxisomes to mitochondria. Moreover, peroxisome deficiency greatly enhanced the induction of apoptosis by etoposide, whereas 4-PBA treatment attenuated etoposide-induced caspase activation. These results suggest that peroxisomes suppress the mitochondrion-dependent apoptotic pathway in the presence of DNA damage. Together, our data unveil a new function for peroxisomes in the regulation of mitochondrial dynamics and mitochondrion-dependent cell death. Given that mutations of peroxin genes are responsible for lethal disorders such as Zellweger syndrome, the identification of this function of peroxisomes may shed light on the pathogenesis of these diseases.