Fig. 6: Heterozygous (D620N) mutation of VPS35 causes abnormal morphology and dysfunction of mitochondria. | Cell Death & Disease

Fig. 6: Heterozygous (D620N) mutation of VPS35 causes abnormal morphology and dysfunction of mitochondria.

From: (D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model

Fig. 6

A In contrast to intact morphology of mitochondria observed in neuromelanin-positive SNpc DAergic cells of age-matched WT mice, fragmented mitochondria with a reduced size were found in neuromelanin organelle-containing SNpc DAergic neurons of heterozygous VPS35D620N/+ mice aged 16 months. Arrow and star indicate mitochondria and neuromelanin organelle, respectively. Each bar represents mean ± S.E. value of 200 mitochondria. **P < 0.01 compared with WT mice. B Confocal immunofluorescence staining of Tom20 showed that mitochondria in TH-positive SNpc DAergic neurons of WT mice exhibited a long thread-like structure. In contrast, truncated and shortened mitochondria were found in TH-positive SNpc DAergic neurons of VPS35D620N/+ mice at age of 16 months. Each bar shows mean ± S.E. value of 80 neurons from four mice. *P < 0.05 compared with WT mice. C Immunoblotting assays demonstrated that protein expression of mitochondrial mitofusin 2 was downregulated in SN of VPS35D620N/+ knockin mice aged 16 months. Downregulated expression of mitofusin 2 was not found in SN of 12-month-old VPS35D620N/+ mice. Level of mitochondrial Drp1 was not altered in SN of VPS35D620N/+ mice at age of 12 or 16 months. COX IV is a protein marker of mitochondrial fraction. Each bar shows mean ± S.E. value of six mice. ***P < 0.001 compared with WT mice. D Confocal double immunofluorescence staining demonstrated that protein expression of mitofusin 2 was downregulated in TH-positive SNpc DAergic neurons of VPS35D620N/+ knockin mice aged 16 months. Each bar represents mean ± S.E. value of 80 neurons from four mice. E Mitochondrial complex I or complex IV activity was reduced in SN of 16-month-old heterozygous VPS35D620N/+ mice. Each bar represents mean ± S.E. value of six mice. F Intracellular level of ATP was decreased in SN of VPS35D620N/+ knockin mice at age of 16 months. Each bar shows mean ± S.E. value of six mice. G Compared to WT mice, reduced basal oxygen consumption rate was observed in SN of 16-month-old VPS35D620N/+ mice. Each bar represents mean ± S.E. value of three mice.

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