期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1867, 期 7, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2020.118709
关键词
Peroxisomes; Mitochondria; Organelle division; MFF; PEX14; Redox homeostasis; Pexophagy
资金
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/N01541X/1, BB/R016844/1]
- European Union [812968 PERICO]
- Research Foundation Flanders [1213620N, G095315N]
- German Research Foundation (DFG) [D10043030, SFB 1134, 397476530]
- MEAMEDMA Anschubforderung, Medical Faculty Mannheim, University of Heidelberg
- Medical Research Council [MR/P022405/1]
- Wellcome Trust Institutional Strategic Support Award [WT105618MA]
- KU Leuven [PDM/18/188]
- Zellweger UK
- Sidney Perry Foundation
- Devon Educational Trust
- BBSRC [BB/N01541X/1, BB/R016844/1] Funding Source: UKRI
- MRC [MR/P022405/1] Funding Source: UKRI
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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