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. 2008 Feb 5;105(5):1638-43.
doi: 10.1073/pnas.0709336105. Epub 2008 Jan 29.

The PINK1/Parkin pathway regulates mitochondrial morphology

Angela C Poole  1 , Ruth E Thomas, Laurie A Andrews, Heidi M McBride, Alexander J Whitworth, Leo J Pallanck
Affiliations

The PINK1/Parkin pathway regulates mitochondrial morphology

Angela C Poole et al. Proc Natl Acad Sci U S A. .

Abstract

Loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) or parkin genes, which encode a mitochondrially localized serine/threonine kinase and a ubiquitin-protein ligase, respectively, result in recessive familial forms of Parkinsonism. Genetic studies in Drosophila indicate that PINK1 acts upstream of Parkin in a common pathway that influences mitochondrial integrity in a subset of tissues, including flight muscle and dopaminergic neurons. The mechanism by which PINK1 and Parkin influence mitochondrial integrity is currently unknown, although mutations in the PINK1 and parkin genes result in enlarged or swollen mitochondria, suggesting a possible regulatory role for the PINK1/Parkin pathway in mitochondrial morphology. To address this hypothesis, we examined the influence of genetic alterations affecting the machinery that governs mitochondrial morphology on the PINK1 and parkin mutant phenotypes. We report that heterozygous loss-of-function mutations of drp1, which encodes a key mitochondrial fission-promoting component, are largely lethal in a PINK1 or parkin mutant background. Conversely, the flight muscle degeneration and mitochondrial morphological alterations that result from mutations in PINK1 and parkin are strongly suppressed by increased drp1 gene dosage and by heterozygous loss-of-function mutations affecting the mitochondrial fusion-promoting factors OPA1 and Mfn2. Finally, we find that an eye phenotype associated with increased PINK1/Parkin pathway activity is suppressed by perturbations that reduce mitochondrial fission and enhanced by perturbations that reduce mitochondrial fusion. Our studies suggest that the PINK1/Parkin pathway promotes mitochondrial fission and that the loss of mitochondrial and tissue integrity in PINK1 and parkin mutants derives from reduced mitochondrial fission.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
drp1 is a parkin and PINK1 enhancer. (A) A stock bearing the parkin null allele park25 was mated to another stock that also carried the park25 allele and a given drp1 allele in trans to a recombination-suppressing chromosome bearing the dominant marker Cy (designated CyO). For each drp1 allele tested, the percentage of Cy (drp1+/+) and non-Cy (drp1+/−) park25/park25 offspring that resulted from the cross is shown. (B) Female flies heterozygous for the PINK1B9 deletion allele were mated to flies bearing a given drp1 allele in trans to the CyO chromosome and the percentage of Cy (drp1+/+) and non-Cy (drp1+/−) PINK1B9 hemizygous offspring (the PINK1 gene is on the X chromosome) is shown. (C) A WT fly stock was mated to flies bearing a given drp1 allele in trans to the CyO chromosome, and the percentage of Cy (drp1+/+) and non-Cy (drp1+/−) offspring that resulted is shown. Note that no significant difference from Mendelian expectations is detected in offspring frequency in crosses carried out with the drp1 alleles in a WT parkin and PINK1 background (P = 0.16 for drp1T26 in a WT background; P = 0.67 for drp1KG in a WT background). Genotypes: drp1KG = drp1KG03815. The number of offspring scored from each cross was >100. ***, P < 1 × 10−5. All statistical analyses were performed by using χ2 analysis.
Fig. 2.
Fig. 2.
Increased drp1 gene dosage and loss-of-function mutations in opa1 and mfn2 suppress the parkin and PINK1 mutant phenotypes. (A) The frequency of adult flies of the indicated genotypes that lack thoracic indentations. (B) The frequency of adult flies of the indicated genotypes capable of flight. (C) The climbing ability of adult flies of the given genotypes. Genotypes: drp1TGnt = drp1 transgene; drp1TGt = epitope-tagged drp1 transgene; opa1S3 = opa1l(2)S3475; opa1f0 = opa1f02779; mfn2Df = Df (1)Excel6239. n = number of animals of the given genotypes analyzed. Statistical analysis was done by using Student's t test. *, P < 0.05; **, P < 0.001; ***, P < 1 × 10−5. Error bars indicate the SEM.
Fig. 3.
Fig. 3.
Genetic perturbations of mitochondrial fission and fusion components modified the PINK1 eye overexpression phenotype. (A) Compound eye from a WT fly showing regular arrangement of ommatidia. (B) Compound eye from a fly overexpressing PINK1 showing disruption of ommatidial structure. (C) Compound eye from a fly expressing a mfn2-inverted repeat (mfn2-IR) demonstrates that perturbation of Mfn2 had no effect on eye morphology. (D–F) A heterozygous deletion that removes the drp1 gene (D), a point mutation of drp1 (E), and an inverted repeat targeting the drp1 transcript (F) all suppress the PINK1 eye overexpression phenotype. (G–I) A heterozygous mutation of opa1 (G), a deletion of the mfn2 gene (H), and an inverted repeat targeting the mfn2 transcript (I) all enhance the PINK1 eye overexpression phenotype. Genotypes: drp1Df = Df(2L)C144; opa1S3 = opa1l(2)S3475; mfn2Df = Df (1)Excel6239.
Fig. 4.
Fig. 4.
Increased drp1 gene dosage and decreased opa1 gene dosage suppress the mitochondrial morphological defects of PINK1 and parkin mutants. For each of the designated genotypes, transverse sections of one-day old adult flight muscle were examined using transmission electron microscopy. (A) Flight muscle from WT flies show regular arrangement of myofibrils (arrows) and densely packed mitochondria (arrowheads) with intact cristae. (Scale bar, 200 nm. All other images are at the same scale.) (B–F) Both increased drp1 gene dosage (D) and decreased opa1 gene dosage (E and F) substantially suppress the morphological defects seen in PINK1 (B) and parkin (C) mutants alone.
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