Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation
Passmore, J; Carmichael, R; Schrader, T; et al.Godinho, L; Ferdinandusse, S; Lismont, C; Wang, Y; Hacker, C; Islinger, M; Fransen, M; Richards, DM; Freisinger, P; Schrader, M
Date: 26 March 2020
Journal
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier
Publisher DOI
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 ...
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.
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