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

Background

The dynamics of mitochondria and peroxisomes is a tightly regulated process that allows the cell to adapt to different nutritional and environmental conditions efficiently. These cellular organelles were seen as static inside the cell for many years, but now we know that they can adopt various structures, ranging from small, spherical particles to long, interconnected filaments. The division of organelles by a process called fission consists of membrane elongation of an existing organelle, constriction, and membrane fission. There are several proteins involved in the fission of mitochondria and peroxisomes, such as DRP1, MFF, and FIS. The mechanism of peroxisomal fission is similar to the mitochondrial one but with some particular differences. For example, PEX11β is required to assemble division factors at the peroxisomal membrane. Importantly, mutations in the genes that encode these division factors cause diseases that often present with neurological abnormalities. As one can imagine, mutations in genes that encode for proteins that participate in the division of both organelles affect mitochondria and peroxisomes. However, the characteristic biochemical functions of these organelles are commonly not affected in these patients, suggesting that alterations in organelle dynamics are the main contributors to the pathophysiological processes of these diseases.

One good example is present in patients with mutations in MFF (mitochondrial fission factor). These patients do not show severe alterations in mitochondrial functions, demonstrated by no changes in OXPHOS functions, redox metabolism, or mitochondrial DNA (mtDNA) and ATP levels (1,2). In the same line, analysis of peroxisomal biochemical functions in other MFF-deficient patients did not show severe abnormalities (2,3).

Could impaired peroxisomal plasticity contribute in a major way to the pathophysiology of MFF-deficient patients? That is the question that Passmore et al. tried to answer in this recent study (4).

 

The findings

To unravel the contribution of peroxisomal plasticity to the pathophysiology of MFF-deficient patients they used Mff-deficient cells obtained from these patients. Peroxisomal biochemical abnormalities were not present in skin fibroblasts from patients with MFF deficiency, similar to what was observed in MFF-deficient patients (2,3). They found that the levels of specific metabolites that are exclusively metabolized in the peroxisome were similar between control and MFF-deficient cells. Peroxisomes have a membrane, and the matrix proteins inside the organelle need to be imported from the cytosol. This process is altered in peroxisome biogenesis disorders but, in MFF-deficient cells, the import of two prototypical peroxisomal proteins such as ACOX1 and ACAA1 was not affected. As part of the tight regulation of the number and size of cellular organelles, peroxisomes can also undergo an autophagic process. In MFF-deficient cells, peroxisomes are elongated due to a defect in the organelle division. However, the removal of peroxisomes by autophagic processes was equal between controls and MFF-deficient cells. They measured the removal of peroxisomes by growing cells under starvation conditions, which triggers this removal, and then adding back a nutrient-enriched culture media. They also used a fragment of a peroxisomal biogenesis protein (PEX3) which is known to induce the removal of peroxisomes.

What they found is that the import of peroxisomal proteins into the elongated segment of the peroxisomes was less efficient in MFF-deficient cells. Catalase fluorescent signal, an enzyme present in the peroxisomal matrix, was lower in the tubular protrusion emerging from the spherical body. The fluorescent signal of a genetically modified GFP that is transported into the peroxisome was also weaker. However, the elongated tubule was enriched in PEX14, which they found that helped to stabilize this structure to microtubules.

Why I liked this study

We still need to learn so much about the roles of peroxisomes in health and disease. Most of the studies are focused on the relation between the biochemical functions of the peroxisomes and their associated disorders. However, the contribution of peroxisomal dynamics to diseases is not well known. This study sheds some light on the alterations caused by mutations in one of the fission factors involved in peroxisomal dynamics, MFF. The key fact that biochemical functions related to mitochondria and peroxisomes are not altered in patients with MFF mutations led these researchers to investigate the effect of this mutation in peroxisomal dynamics. They confirmed that the biochemical functions are not altered but the distribution of peroxisomes is, as well as some other peroxisomal functions, such as those associated with redox metabolism. Another interesting observation was the cell-type specific differences in peroxisomal shape in MFF-deficient cells. These findings open new avenues of research focused on the study of the dynamics of these organelles, rather than the classical biochemical functions performed by peroxisomes.

 

References

1. Shamseldin HE, Alshammari M, Al-Sheddi T, Salih MA, Alkhalidi H, Kentab A, et al. Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. J Med Genet. 2012 Apr;49(4):234–41.
2. Nasca A, Legati A, Baruffini E, Nolli C, Moroni I, Ardissone A, et al. Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy. Hum Mutat. 2016;37(9):898–903.
3. Koch J, Feichtinger RG, Freisinger P, Pies M, Schrödl F, Iuso A, et al. Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral neuropathy. J Med Genet. 2016 Apr;53(4):270–8.
4. Passmore JB, Carmichael RE, Schrader TA, Godinho LF, Ferdinandusse S, Lismont C, et al. Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation. bioRxiv. 2020 Mar 25;2020.01.08.898486.

Tags: mff, mitochondria, organelle, peroxisome

doi: https://doi.org/10.1242/prelights.18018

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