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

Autor: Luis F. Godinho, Celien Lismont, Ruth E. Carmichael, Marc Fransen, Peter Freisinger, Christian Hacker, Markus Islinger, Yunhong Wang, Michael Schrader, Sacha Ferdinandusse, Josiah B. Passmore, David M. Richards, Tina A. Schrader
Přispěvatelé: Laboratory Genetic Metabolic Diseases, AGEM - Inborn errors of metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Jazyk: angličtina
Rok vydání: 2020
Předmět:
MFF
Mitochondrial fission factor
Regulator
PMP
peroxisomal membrane protein
Mitochondrion
Biology
PEX14
PBD
peroxisome biogenesis disorder
PED
single peroxisomal enzyme deficiency
Mitochondrial Dynamics
Organelle division
Article
PTS
peroxisome targeting signal
GTP Phosphohydrolases
ER
endoplasmic reticulum
Mitochondrial Proteins
03 medical and health sciences
ROS
reactive oxygen species
0302 clinical medicine
MFF
mitochondrial fission factor
Organelle
Autophagy
Peroxisomes
Humans
Compartment (development)
FIS1
mitochondrial fission 1 protein
Molecular Biology
030304 developmental biology
0303 health sciences
Membrane Proteins
Cell Biology
VLCFA
very-long-chain fatty acid
Peroxisome
DRP1
dynamin-related protein 1
Lipid Metabolism
Pathophysiology
Cell biology
Mitochondria
ACOX1
acyl-CoA oxidase 1
Pexophagy
Reactive Oxygen Species
Microtubule-Associated Proteins
030217 neurology & neurosurgery
Function (biology)
Redox homeostasis
Zdroj: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 1867(7):118709. Elsevier
Biochimica et Biophysica Acta. Molecular Cell Research
ISSN: 0167-4889
DOI: 10.1101/2020.01.08.898486
Popis: 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.
Graphical abstract Unlabelled Image
Highlights • Peroxisomes are highly elongated in cells from patients lacking fission factor MFF. • Peroxisomal proteins are not uniformly distributed in highly elongated peroxisomes. • Peroxisomal metabolism is unaltered in MFF-deficient patients. • Peroxisomal elongations are stabilised through interaction with microtubules. • Highly elongated peroxisomes are not spared from degradation.
Databáze: OpenAIRE
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