A Lethal Defect of Mitochondrial and Peroxisomal Fission

Abstract

We report on a newborn girl with microcephaly, abnormal brain development, optic atrophy and hypoplasia, persistent lactic acidemia, and a mildly elevated plasma concentration of very-long-chain fatty acids. We found a defect of the fission of both mitochondria and peroxisomes, as well as a heterozygous, dominant-negative mutation in the dynamin-like protein 1 gene (DLP1). The DLP1 protein has previously been implicated, in vitro, in the fission of both these organelles. Overexpression of the mutant DLP1 in control cells reproduced the fission defect. Our findings are representative of a class of disease characterized by defects in both mitochondria and peroxisomes.

PEX14 is required for microtubule-based peroxisome motility in human cells

“…This is due to the fact that: (1) some peroxins are present in functionally overlapping forms, like the ubiquitin-conjugating enzymes of the peroxisomal protein import machinery (Grou et al, 2008) and (2) other peroxins have different cellular functions in addition to their peroxisome-specific roles and thus, inactivation of the corresponding genes lead to more generalized cellular defects and severe human diseases that are not immediately recognized as PBDs. These processes include peroxisome fission, regulated degradation, inheritance and motility, which require proteins that are also necessary for the maintenance of other organelles (Fagarasanu et al, 2009;Farre et al, 2009;Waterham et al, 2007). Thus, because of the functional redundancy of peroxins and the sharing of peroxins by different organelles, other strategies have to be employed to identify such peroxins with overlapping function.…”

“…So far, 12 complementation groups of peroxisome biogenesis disorders (PBDs) have been identified and studied in detail (Steinberg et al, 2006). Notably, with the exception of a gene coding for a protein of the peroxisomal fission machinery (Waterham et al, 2007), all genes affected in these patients encode proteins required for the import of matrix and membrane proteins into peroxisomes. Proteins that are required for peroxisome biogenesis are collectively called peroxins (PEX), and three of them, PEX3, PEX16 and PEX19, are necessary for the targeting and insertion of peroxisomal membrane proteins (Ma and Subramani, 2009).…”

De la levure aux maladies neurodégénératives

“…En 2007, une mutation a aussi été détectée dans le gène DRP1 (dynamin-related protein 1), le troisième acteur majeur de la dynamique mitochondriale, impliqué dans la fission des mitochondries, chez un nouveau-né décédé à l'âge de 6 mois présentant un syndrome très sévère associant une microcéphalie, des anomalies du développement cérébral, une atrophie optique, une hypoplasie et une acidose lactique [4]. Les fibroblastes de ce nouveau-né présentaient un réseau mitochondrial et des peroxysomes hyperfusionnés, la particularité de DRP1 étant de participer à la fission de ces deux organites.…”

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

“…The membrane fusion GTPases OPA1 and mitofusin 2 (MFN2) are frequently found mutated in cases of dominant optic atrophy (DOA) and Charcot-MarieTooth disease type 2A, respectively, two distinct types of neuropathies (Alexander et al , 2000 ;Delettre et al , 2000 ;Z ü chner et al, 2004 ;Chen and Chan , 2006 ;Olichon et al , 2006 ;Chen et al , 2007 ;Feely et al , 2011 ) . Mutations affecting the mitochondrial fission factor dynamin-related protein 1 (DRP1) are connected to cardiomyopathy and to a neonatal lethal case of multisymptomatic disease with microencephaly and optic atrophy (Detmer and Chan , 2007 ;Waterham et al , 2007 ;Ashrafian et al , 2010 ;Westermann , 2010 ). The connection between fusion/fission proteins and the pathogenesis of the diseases is not fully understood.…”