Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent apoptosis pathway

Abstract

Peroxisomes cooperate with mitochondria in the performance of cellular metabolic functions, such as fatty acid oxidation and the maintenance of redox homeostasis. However, whether peroxisomes also regulate mitochondrial fission-fusion dynamics or mitochondriondependent apoptosis remained unclear. We now show that genetic ablation of the peroxins Pex3 or Pex5, which are essential for peroxisome biogenesis, results in mitochondrial fragmentation in mouse embryonic fibroblasts (MEFs) in a manner dependent on Drp1 (also known as DNM1L). Conversely, treatment with 4-PBA, which results in peroxisome proliferation, resulted in mitochondrial elongation in wild-type MEFs, but not in Pex3-knockout MEFs. We further found that peroxisome deficiency increased the levels of cytosolic cytochrome c and caspase activity under basal conditions without inducing apoptosis. It also greatly enhanced etoposide-induced caspase activation and apoptosis, which is indicative of an enhanced cellular sensitivity to death signals. Taken together, our data unveil a previously unrecognized role for peroxisomes in the regulation of mitochondrial dynamics and mitochondrion-dependent apoptosis. Effects of peroxin gene mutations on mitochondrion-dependent apoptosis may contribute to pathogenesis of peroxisome biogenesis disorders. This article has an associated First Person interview with the first author of the paper.

Fatty Liver Due to Increased de novo Lipogenesis: Alterations in the Hepatic Peroxisomal Proteome

“…It has been shown that this is a more complex process, including the development of pre-peroxisomes originated from mitochondria, which fuse with endoplasmic vesicles from the ER for maturation by a PEX3 cycling process (Sugiura et al, 2017). On the other hand, the specific loss of hepatic peroxisomes, e.g., in liver-specific PEX5 –/– KO mice, leads to mitochondrial malformation or function in the liver but not in other physiological relevant tissues (Dirkx et al, 2005; Shinde et al, 2018; Tanaka et al, 2019). This indicates that the generation of peroxisomes is functionally closely related to the mitochondria.…”

“…This process involves the budding of endoplasmatic reticulum (ER) and the import of cytosolically translated proteins, so that the unambiguous assignment of proteins to distinct organelle structure becomes more and more difficult (van der Zand et al, 2012; Schrader et al, 2013; Tabak et al, 2013). Moreover, mitochondria are also integrated in this flowing process (Dirkx et al, 2005; Tanaka et al, 2019). In addition, the close proximity of peroxisomes to lipid droplets led to an interaction of cellular structures to transfer lipids for degradation, but also the bilateral process is possible to exchange specific lipids (Binns et al, 2006; Bartz et al, 2007; Pu et al, 2011).…”

Modulation of Tmem135 Leads to Retinal Pigmented Epithelium Pathologies in Mice

“…Physical contacts between peroxisomes and mitochondria have been well studied, 43 , 44 and more importantly, a recent study indicated that mitochondrial fission could be regulated by peroxisomes. 45 Based on these notions, it is possible that TMEM135 functions in peroxisomes and its perturbation may, in turn, affect mitochondrial dynamics. Alternatively, TMEM135 may have multiple molecular functions, and RPE phenotypes we have observed may be in part caused by a defect in a different function/pathway.…”

When Friendship Turns Sour: Effective Communication Between Mitochondria and Intracellular Organelles in Parkinson's Disease

“…Wang et al demonstrated that excessive ROS production by peroxisomes led to mitochondria-induced cell death in Pex19p-deficient human fibroblasts and that this process may be countered by targeted overexpression of select antioxidant enzymes: peroxisomal glutathione S-transferase Kappa 1, SOD1, and mitochondrial catalase (Wang et al, 2013). Similarly, Peeters et al demonstrated disruption of peroxisome biogenesis in hepatocyte-selective Pex5 knockout mice to damage MIM, deplete mtDNA, reduce or incomplete respiratory chain complexes I, III, and V, increase oxidative stress, increase mitochondrial membranes permeability and fluidity, and increase mitochondrial biogenesis (Peeters et al, 2015;Tanaka et al, 2019). Both peroxisome and mitochondrial dysfunction and dysregulated ROS balance is important in the occurrence of age-related disease (Cipolla and Lodhi, 2017).…”