Fission Impossible (?)—New Insights into Disorders of Peroxisome Dynamics

Abstract

Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane-shaping protein PEX11β and division proteins, such as the membrane adaptors FIS1 and MFF, which recruit the fission GTPase DRP1 to the peroxisomal membrane. The latter proteins are also involved in mitochondrial division. Patients with loss of DRP1, MFF or PEX11β function have been identified, showing abnormalities in peroxisomal (and, for the shared proteins, mitochondrial) dynamics as well as developmental and neurological defects, whereas the metabolic functions of the organelles are often unaffected. Here, we provide a timely update on peroxisomal membrane dynamics with a particular focus on peroxisome formation by membrane growth and division. We address the function of PEX11β in these processes, as well as the role of peroxisome–ER contacts in lipid transfer for peroxisomal membrane expansion. Furthermore, we summarize the clinical phenotypes and pathophysiology of patients with defects in the key division proteins DRP1, MFF, and PEX11β as well as in the peroxisome–ER tether ACBD5. Potential therapeutic strategies for these rare disorders with limited treatment options are discussed.

The peroxisome: an update on mysteries 3.0

“…Similarities and differences between peroxisomal and mitochondrial division have recently been reviewed (Subramani et al 2023 ). Patients with a loss of DRP1, MFF or PEX11β function have been identified who suffer from neurological abnormalities and exhibit elongated peroxisomes (and mitochondria—in DRP1 and MFF deficiency) due to impaired organelle dynamics (recently reviewed in Carmichael et al 2022 ).

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“…Peroxisome-ER tethering, mediated via the ACBD5-VAPB tether protein interaction in mammals (Figs. 1 and 4 ) (see “ Mysterious shapers, movers, and regulators of peroxisome dynamics ”), is important for human health, given the pathologies observed in ACBD5-deficient patients (Carmichael et al 2022 ). An ACBD5-deficient mouse model ( Acbd5 −/− ) has recently been developed to characterise the pathological changes in various tissues, providing a better understanding of how loss of ACBD5 leads to disease symptoms (Darwisch et al 2020 ).…”

“…The physiological, clinical, diagnostic, and treatment aspects of peroxisomal disorders have been covered in recent reviews (Wanders et al 2017 , 2023 ; Wanders 2018 ; Cheillan 2020 ; Honsho et al 2020b ; Steinberg et al 2020 ; Bose et al 2022 ). Recently discovered new peroxisomal disorders such as deficiencies of ABCD3 (PMP70) (Ferdinandusse et al 2015 ), ACBD5 (Yagita et al 2017 ; Ferdinandusse et al 2017 ; Darwisch et al 2020 ) (see “ Mysterious shapers, movers, and regulators of peroxisome dynamics ”), and ACOX3 (Kim et al 2020 ) were also addressed elsewhere (Wanders 2018 ; Carmichael et al 2022 ; Wanders et al 2023 ) (Fig. 1 ).…”

Organelle Membrane Extensions in Mammalian Cells

“…The formation of peroxisomes by growth and division out of pre-existing organelles follows a multi-step process, which involves membrane deformation and elongation, constriction and final division, with PEX11β playing roles in all steps. Loss of DRP1 or MFF function, as observed in patients with defects in peroxisomal (and mitochondrial) dynamics, results in highly elongated peroxisomes (and mitochondria) (reviewed in [51]). In particular, the loss of MFF, a major membrane adaptor for DRP1, causes the formation of hyper-elongated peroxisomal membrane protrusions, which emanate from a spherical peroxisome (Figure 1).…”

“…It should be noted that the peroxisome-ER membrane contacts also fulfil metabolic functions, e.g., in cooperative ether lipid synthesis between peroxisomes and the ER, as well as in fatty acid metabolism. Patients with a defect in ACBD5 have been identified and suffer from leukodystrophy and retinopathy [51,66,67]. These patients show an accumulation of very-long-chain fatty acids (VLCFA), which can only be degraded in peroxisomes via the peroxisomal β-oxidation pathway.…”