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

Abstract

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

Genetic disorders of cellular trafficking

“…In the same sense, the role of the mitochondrial Rho-GTPases, Miro, in peroxisomal dynamics has been recently described. Conversely, the microtubule-dependent transport of peroxisomes and mitochondria uses different machineries [38,39].…”

Maintaining social contacts: The physiological relevance of organelle interactions

“…Mutations in the shared peroxisome/mitochondria organelle division factors such as DRP1/DNML1 and MFF (see Section 2.1.1 ) can result in severe disorders with neurological abnormalities and are characterised by defects in the membrane dynamics and division of peroxisomes (and mitochondria) rather than by loss of metabolic functions [ [158] , [159] , [160] , [161] ]. The hyper-elongation of peroxisomes in MFF-deficient fibroblasts has been suggested to result from a constant ER-peroxisome lipid flow via VAP-ACBD5 MCSs [ 149 , 161 , 162 ]. As peroxisomes cannot divide due to the loss of functional MFF, lipid supply from the ER causes a pronounced expansion of the peroxisomal membrane.…”