Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation

Josiah B Passmore,Ruth E Carmichael,Tina A Schrader,Luis F Godinho,Sacha Ferdinandusse,Celien Lismont,Yunhong Wang,Christian Hacker,Markus Islinger,Marc Fransen,David M Richards,Peter Freisinger,Michael Schrader

doi:10.1016/j.bbamcr.2020.118709

Abstract

Peroxisomes are highly dynamic subcellular compartments with important functions in lipid and ROS metabolism. Impaired peroxisomal function can lead to severe metabolic disorders with developmental defects and neurological abnormalities. Recently, a new group of disorders has been identified, characterised by defects in the membrane dynamics and division of peroxisomes rather than by loss of metabolic functions. However, the contribution of impaired peroxisome plasticity to the pathophysiology of those disorders is not well understood. Mitochondrial fission factor (MFF) is a key component of both the peroxisomal and mitochondrial division machinery. Patients with MFF deficiency present with developmental and neurological abnormalities. Peroxisomes (and mitochondria) in patient fibroblasts are highly elongated as a result of impaired organelle division. The majority of studies into MFF-deficiency have focused on mitochondrial dysfunction, but the contribution of peroxisomal alterations to the pathophysiology is largely unknown. Here, we show that MFF deficiency does not cause alterations to overall peroxisomal biochemical function. However, loss of MFF results in reduced import-competency of the peroxisomal compartment and leads to the accumulation of pre-peroxisomal membrane structures. We show that peroxisomes in MFF-deficient cells display alterations in peroxisomal redox state and intra-peroxisomal pH. Removal of elongated peroxisomes through induction of autophagic processes is not impaired. A mathematical model describing key processes involved in peroxisome dynamics sheds further light into the physical processes disturbed in MFF-deficient cells. The consequences of our findings for the pathophysiology of MFF-deficiency and related disorders with impaired peroxisome plasticity are discussed.

Highlights

Peroxisomes are highly dynamic membrane-bound organelles with key functions in cellular lipid and reactive oxygen species (ROS) metabolism
The elongation of peroxisomes in Mitochondrial fission factor (MFF)-deficient fibroblasts has been suggested to be the result of a constant lipid flow from the endoplasmic reticulum (ER) to peroxisomes via membrane contact sites, which are mediated by peroxisomal ACBD5 and ER-resident VAPB (Costello et al 2017b)
Whereas dysfunctional peroxisome metabolism and associated diseases are generally well studied, the consequences and pathophysiology caused by specific disruption to peroxisome dynamics and plasticity are less clear

Summary

Introduction

Peroxisomes are highly dynamic membrane-bound organelles with key functions in cellular lipid and ROS metabolism. Peroxisome biogenesis disorders (PBDs) result from mutations in PEX genes, which encode proteins essential for peroxisomal membrane biogenesis and matrix protein import. PBDs, such as Zellweger Spectrum disorders, are usually characterised by a loss of functional peroxisomes. This impacts on multiple metabolic pathways (e.g., peroxisomal α- and β-oxidation of fatty acids, and the synthesis of ether-phospholipids, which are abundantly present in myelin sheaths) and results in various patient phenotypes and symptoms (Braverman et al 2016). Peroxisomal single enzyme deficiencies (PEDs) on the other hand are caused by mutations in genes encoding a specific peroxisomal enzyme/protein and usually affect one metabolic pathway or function.

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