Mammalian cells typically contain hundreds of peroxisomes but can increase peroxisome abundance further in response to extracellular stimuli. We report here the identification and characterization of two novel human peroxisomal membrane proteins, PEX11␣ and PEX11␤. Overexpression of the human PEX11␤ gene alone was sufficient to induce peroxisome proliferation, demonstrating that proliferation can occur in the absence of extracellular stimuli and may be mediated by a single gene. Time course studies indicated that PEX11␤ induces peroxisome proliferation through a multistep process involving peroxisome elongation and segregation of PEX11␤ from other peroxisomal membrane proteins, followed by peroxisome division. Overexpression of PEX11␣ also induced peroxisome proliferation but at a much lower frequency than PEX11␤ in our experimental system. The patterns of PEX11␣ and PEX11␤ expression were examined in the rat, the animal in which peroxisome proliferation has been examined most extensively. Levels of PEX11␤ mRNA were similar in all tissues examined and were unaffected by peroxisomeproliferating agents. Conversely, PEX11␣ mRNA levels varied widely among different tissues, were highest in tissues that are sensitive to peroxisome-proliferating agents, and were induced more than 10-fold in response to the peroxisome proliferators clofibrate and di(2-ethylhexyl) phthalate. Taken together, these data implicate PEX11␤ in the constitutive control of peroxisome abundance and suggest that PEX11␣ may regulate peroxisome abundance in response to extracellular stimuli.Peroxisomes are ubiquitous components of eukaryotic cells, absent only from mature erythrocytes and certain primitive unicellular eukaryotes. One of the more intriguing aspects of peroxisome biogenesis is how cells control the abundance of this organelle. Mammalian cells contain hundreds of peroxisomes under normal growth conditions, suggesting that there are constitutive mechanisms for raising peroxisome abundance above one per cell. In addition, peroxisome abundance may change in response to extracellular stimuli, indicating the existence of a signal transduction pathway that exerts additional control over peroxisome abundance. Inducers of peroxisome proliferation include both hypolipidemic drugs (e.g. clofibrate) and plasticizing agents (e.g. di(2-ethylhexyl) phthalate (DEHP) 1 ), which act through PPAR␣, the ␣ isoform of the peroxisome proliferator-activated receptor (1-3). PPAR␣ is a member of the nuclear hormone receptor superfamily and functions as a heterodimer with retinoid X receptor (RXR), another nuclear hormone receptor. The activated PPAR␣⅐RXR heterodimer binds peroxisome proliferator-responsive elements (PPREs) and mediates transcriptional activation of a large array of PPRE-containing genes in a drug-dependent manner (4). However, the pathway between altered gene expression and peroxisome proliferation remains to be elucidated.Peroxisome proliferation has also been observed in lower eukaryotes. In the yeast Saccharomyces cerevisiae, fatty acid ox...

The flow of material from peripheral, early endosomes to late endosomes requires microtubules and is thought to be facilitated by the minus end-directed motor cytoplasmic dynein and its activator dynactin. The microtubule-binding protein CLIP-170 may also play a role by providing an early link to endosomes. Here, we show that perturbation of dynactin function in vivo affects endosome dynamics and trafficking. Endosome movement, which is normally bidirectional, is completely inhibited. Receptor-mediated uptake and recycling occur normally, but cells are less susceptible to infection by enveloped viruses that require delivery to late endosomes, and they show reduced accumulation of lysosomally targeted probes. Dynactin colocalizes at microtubule plus ends with CLIP-170 in a way that depends on CLIP-170’s putative cargo-binding domain. Overexpression studies using p150Glued, the microtubule-binding subunit of dynactin, and mutant and wild-type forms of CLIP-170 indicate that CLIP-170 recruits dynactin to microtubule ends. These data suggest a new model for the formation of motile complexes of endosomes and microtubules early in the endocytic pathway.

Peroxisomes and mitochondria are ubiquitous, highly dynamic organelles with an oxidative type of metabolism in eukaryotic cells. Over the years, substantial evidence has been provided that peroxisomes and mitochondria exhibit a close functional interplay which impacts on human health and development. The so‐called “peroxisome‐mitochondria connection” includes metabolic cooperation in the degradation of fatty acids, a redox‐sensitive relationship, an overlap in key components of the membrane fission machineries and cooperation in anti‐viral signalling and defence. Furthermore, combined peroxisome‐mitochondria disorders with defects in organelle division have been revealed. In this review, we present the latest progress in the emerging field of peroxisomal and mitochondrial interplay in mammals with a particular emphasis on cooperative fatty acid β‐oxidation, redox interplay, organelle dynamics, cooperation in anti‐viral signalling and the resulting implications for disease.

Peroxisomes are remarkably dynamic, multifunctional organelles, which react to physiological changes in their cellular environment and adopt their morphology, number, enzyme content and metabolic functions accordingly. At the organelle level, the key molecular machinery controlling peroxisomal membrane elongation and remodeling as well as membrane fission is becoming increasingly established and defined. Key players in peroxisome division are conserved in animals, plants and fungi, and key fission components are shared with mitochondria. However, the physiological stimuli and corresponding signal transduction pathways regulating and modulating peroxisome maintenance and proliferation are, despite a few exceptions, largely unexplored. There is emerging evidence that peroxisomal dynamics and proper regulation of peroxisome number and morphology are crucial for the physiology of the cell, as well as for the pathology of the organism. Here, we discuss several key aspects of peroxisomal fission and proliferation and highlight their association with certain diseases. We address signaling and transcriptional events resulting in peroxisome proliferation, and focus on novel findings concerning the key division components and their interplay. Finally, we present an updated model of peroxisomal growth and division. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.