Editors' ChoiceMitochondria

Meet Up at the Mitochondria

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Science Signaling  17 Jun 2014:
Vol. 7, Issue 330, pp. ec164
DOI: 10.1126/scisignal.2005594

Mitochondria are both producers of cellular energy and regulators of lipid metabolism. Mitochondrial dysfunction is found in neurodegenerative disorders, including Parkinson disease, which affects motor control due to the death of a specific set of dopaminergic neurons. Mitochondria are dynamic organelles undergoing fusion, which involves the protein mitofusin (Mfn), and fission, which involves the protein dynamin-related protein 1 (Drp1). Parkin and the kinase PINK1 regulate mitochondrial dynamics and mitophagy: Parkin is recruited to dysfunctional mitochondrial by PINK1, which is stabilized under conditions of mitochondrial dysfunction, and Parkin mediates the ubiquitylation of multiple mitochondrial proteins, including Mfn, to promote mitophagy. Two groups report the results of experiments initiated using the fruitfly Drosophila melanogaster. Yun et al. characterized a mitochondria-associated ubiquitin and SUMO ligase MUL1, and Ivatt et al. found a connection between lipid synthesis in the endoplasmic reticulum and mitophagy.

Yun et al. found that overexpression of MUL1, but not a ligase-inactive mutant, suppressed the mitochondrial phenotypes associated with loss of PINK1 function in fly dopaminergic neurons and flight muscles. Flies genetically deficient in MUL1 or in which MUL1 was knocked down exhibited elongated mitochondria, indicating a function for MUL1 in promoting mitochondrial fission. Consistent with this function, overexpression of MUL1 resulted in reduced amounts of Mfn both in wild-type flies and in flies deficient in PINK1; knockout of MUL1 resulted in increased amounts of Mfn. Overexpression of Mfn phenocopied defects that occurred in PINK1- or Parkin-deficient flies and these defects were rescued by overexpression of MUL1. Genetic analysis of single and double mutants indicated that the MUL1 and PINK1-Parkin function in parallel pathways. Cultured human cancer cells (HeLa) overexpressing MUL1 had smaller globular mitochondria compared with those not overexpressing MUL1, demonstrating that the role of MUL1 in promoting mitochondrial fission is conserved across species. Furthermore, knockdown or CRISPR/Cas9-mediated knockout of MUL1 stabilized both Mfn1 and Mfn2 in HeLa cells. Although knockout of MUL1 did not affect the recruitment of Parkin to mitochondria in response to chemicals that disrupt mitochondrial function, the knockdown of MUL1 exacerbated the fragmentation and retraction of axons of cortical neurons from Parkin-knockout mice and caused a reduction in mitochondrial membrane potential in the Parkin-knockout neurons. Thus, this study indicated that MUL1 functioned in a parallel pathway to PINK1-Parkin to regulate mitochondrial dynamics and that loss of MUL1 function can exacerbate mitochondrial dysfunction and neurodegeneration associated with loss of function of the PINK1-parkin pathway.

Ivatt et al. provide evidence for a connection between regulation of mitophagy and lipid biosynthesis from a genome-wide RNA interference screen in Drosophila S2 cells for genes that altered the recruitment of Parkin fused to green fluorescent protein (Parkin-GFP) to the mitochondria in response to chemicals, such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP), that disrupt mitochondrial function. Twenty candidate genes were validated to function as positive regulators of mitophagy. Several of these encoded proteins that function in lipid biosynthesis: SREBF1, a transcription factor of the SREBP family that promotes lipid biosynthesis; FBXW7, an E3 ubiquitin ligase that targets SREBP and also functions with Parkin; and GSK3α, a serine-threonine kinase involved in many cellular processes. Knockdown of SREBF1, FBXW7, or GSK3α in HeLa cells reduced mitophagy and Parkin translocation to mitochondria in response to chemical disruption of mitochondrial function. Cells exposed to CCCP and in which either SREBF1 or FBXW7 were knocked down had normal rates of autophagic flux and expression of PINK1, but the mitochondrial membrane potential was lost, confirming that the effects of loss of SREBF1 and FBXW7 were related to mitochondrial dysfunction. Knockdown of SREBF1, but not FBXW7, reduced the abundance of PINK1 and its recruitment to puncta in cells exposed to CCCP. Mitochondria and endoplasmic reticulum exchange lipids and both contribute to lipid metabolism. Supplementing the medium with either cholesterol or cholesterol with fatty acids stabilized PINK1 and restored the accumulation of Parkin in mitochondrial puncta in the SREBF1-knockdown cells exposed to CCCP. SREBF1 was identified in GWAS (genome-wide association studies) of sporadic Parkinson's disease. Thus, the SREBP-mediated lipid biosynthesis pathway positively contributes to mitophagy, which may explain the association of SREBF1 with sporadic Parkinson's disease.

J. Yun, R. Puri, H. Yang, M. A. Lizzio, C. Wu, Z.-H. Sheng, M. Guo, MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. eLife 3, e01958 (2014). [PubMed]

R. M. Ivatt, A. Sanchez-Martinez, V. K. Godena, S. Brown, E. Ziviani, A. J. Whitworth, Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy. Proc. Natl. Acad. Sci. U.S.A. 111, 8494–8499 (2014). [Abstract] [Full Text]

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