PT  - JOURNAL ARTICLE
AU  - Josiah B. Passmore
AU  - Ruth E. Carmichael
AU  - Tina A. Schrader
AU  - Luis F. Godinho
AU  - Sacha Ferdinandusse
AU  - Celien Lismont
AU  - Yunhong Wang
AU  - Christian Hacker
AU  - Markus Islinger
AU  - Marc Fransen
AU  - David M. Richards
AU  - Peter Freisinger
AU  - Michael Schrader
TI  - Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation
AID  - 10.1101/2020.01.08.898486
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.08.898486
4099  - http://biorxiv.org/content/early/2020/03/25/2020.01.08.898486.short
4100  - http://biorxiv.org/content/early/2020/03/25/2020.01.08.898486.full
AB  - 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.