The Peroxisome-Mitochondria Connection: How and Why?

Abstract

Over the past decades, peroxisomes have emerged as key regulators in overall cellular lipid and reactive oxygen species metabolism. In mammals, these organelles have also been recognized as important hubs in redox-, lipid-, inflammatory-, and innate immune-signaling networks. To exert these activities, peroxisomes must interact both functionally and physically with other cell organelles. This review provides a comprehensive look of what is currently known about the interconnectivity between peroxisomes and mitochondria within mammalian cells. We first outline how peroxisomal and mitochondrial abundance are controlled by common sets of cis- and trans-acting factors. Next, we discuss how peroxisomes and mitochondria may communicate with each other at the molecular level. In addition, we reflect on how these organelles cooperate in various metabolic and signaling pathways. Finally, we address why peroxisomes and mitochondria have to maintain a healthy relationship and why defects in one organelle may cause dysfunction in the other. Gaining a better insight into these issues is pivotal to understanding how these organelles function in their environment, both in health and disease.

Keywords: fatty acid oxidation; human disease; interorganelle crosstalk; mitochondria; organelle abundance; organelle dysfunction; peroxisomes; reactive oxygen species.

Figure 1

Peroxisomal and mitochondrial abundance are controlled by common sets of cis- and trans-acting factors. (a) Transcriptional control of peroxisome and mitochondrial biogenesis; (b) De novo peroxisome biogenesis requires mitochondria-derived vesicles; (c) Peroxisomes and mitochondria share components of their fission machinery. Shared and organelle-specific components of the fission machinery are indicated in color and gray, respectively; (d) Defects in peroxisome biogenesis impinge on mitophagy. Decreases and increases in organellar mass are indicated by red downright and upright arrows, respectively. Black horizontal arrows represent the formation of new organelles (left arrows) or the removal of damaged/dysfunctional organelles (right arrows). The red T-bar arrow denotes inhibition. ER, endoplasmic reticulum; FA, fatty acid; FIS1, mitochondrial fission protein; GDAP1, ganglioside-induced differentiation-associated protein; MDVs, mitochondria-derived vesicles; MFF, mitochondrial fission factor; MT, mitochondria/mitochondrial; OMM, outer mitochondrial membrane; OXPHOS, oxidative phosphorylation; PEX11, peroxin 11; PO, peroxisome/peroxisomal; TF, transcription factor.

Figure 2

Schematic model of the mechanisms potentially involved in peroxisome-mitochondrial communication. The yellow and green dots represent peroxisome- and mitochondria-derived molecules, respectively. MCS, membrane contact site; MDV, mitochondria-derived vesicle.

Figure 3

Comparison and interplay of peroxisomal and mitochondrial fatty acid β-oxidation (for details, see Section 4.1). Fatty acid β-oxidation, the NAD(H) redox shuttles, the tricarboxylic acid cycle, and the electron transfer chain are respectively depicted in blue, purple, red, and pink. 1a, acyl-CoA oxidase; 1b, acyl-CoA dehydrogenase; 2, enoyl-CoA hydratase; 3, 3-hydroxyacyl-CoA dehydrogenase; 4, 3-ketoacyl-CoA thiolase. ABCD, ATP-binding cassette transporters of subfamily D; ADP, adenine dinucleotide phosphate; BRCFA, branched-chain fatty acid; CAC, carnitine-acylcarnitine carrier; FAD, flavin adenine dinucleotide; FADH₂, reduced FAD; LCFA, long-chain fatty acid; MCFA, medium-chain fatty acid; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; NRS, NAD(H) redox shuttles; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid; VLCFA, very-long-chain fatty acid.