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. 2017 Aug;12(8):1270-1272.
doi: 10.4103/1673-5374.213546.

Mitochondrial homeostasis in Parkinson's disease - a triumvirate rule?

Chee-Hoe Ng  1 , Liting Hang  1   2 , Kah-Leong Lim  1   3   4
Affiliations

Mitochondrial homeostasis in Parkinson's disease - a triumvirate rule?

Chee-Hoe Ng et al. Neural Regen Res. 2017 Aug.
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
PD genes interact with mitochondrial fission, biogenesis and mitophagy. AMPK is a master energy sensor that is activated by increased cellular AMP to ATP ratio. It participates in mitochondrial homeostasis by phosphorylating some key regulators such as Drp1, Mff, Ulk1, Raptor and PGC-1α. When AMP accumulates such as during starvation, mitophagy is favored and AMPK activates this mechanism via coordinating phosphorylation of Raptor and Ulk1. Alternatively, AMPK activates autophagy through an intermediate step that requires mitochondrial fission via phosphorylating Mff and recruitment of Drp1 (Toyama et al., 2016). In addition, AMPK together with Sirt1 (not shown here), participates in post-transcriptional modification of PGC1α to re-establish mitochondrial population through biogenesis. AMPK can oppose mitochondrial fission directly via inhibiting Drp1 activity. Blocking fission could be a means to elevate cellular ATP. PGC-1α over-expression can result in inhibition of fission and enhanced fusion. Mutations in PD genes such as α-syn, ATP13a2, LRRK2, Parkin, PINK1 disrupt mitochondrial homeostasis along these pathways. Parkin may polyubiquitinate Mff and this targets damaged mitochondria for clearance. Mutations of DJ-1 or α-syn enhanced mitochondrial fragmentation by inducing Drp1 expression or activation, respectively. Neurons which are impaired in mitophagy may accumulate dysfunctional mitochondria and unable to adapt to stress while those inadequate in biogenesis will not be able to cope with energy demand. α-syn: α-Synuclein; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; ATP13a2: ATPase type 13A2; Drp1: dynamin-related protein 1; LRRK2: leucine-rich repeat kinase 2; Mff: mitochondrial fission factor; PD: Parkinson’s disease; PGC-1α: PPARγ coactivator-1 α; PINK1: PTEN-induced putative kinase 1; Sirt1: sirtuin 1; Ulk1: unc-51-like kinase 1.
Figure 2
Figure 2
Transcriptional repression of PGC-1α by PD genes, mitochondrial insults and neuroinflammation. Nuclear α-syn can bind directly to PGC-1α promoter, resulting in repression of PGC-1α transcription (Siddiqui et al., 2012). α-syn A53T and mitochondrial toxin (MToxin) can induce N-nitrosylation of transcription factor MEF2C, inhibiting transcriptional activation of PGC-1α (Ryan, 2013). Parkin and Omi, target PARIS and GSK3β for degradation, respectively (Shin et al., 2011; Xu et al., 2014). PARIS acts as a repressor of PGC-1α promoter, while GSK3β promotes PGC-1α degradation. Finally, palmitate, a pro-inflammatory fatty acid, could elicit epigenetic modification by methylating cytosine in PGC-1α promoter in primary cortical neurons, astrocytes and microglial cells (Su et al., 2015). This modification represses PGC-1α expression, giving rise to reduce mitochondrial biogenesis and aberrant fission/fusion. It remains unclear if any of these have impact on autophagy. α-syn: α-Synuclein; GSK3β: glycogen synthase kinase 3β; MEF2C: myocyte enhancer factor 2C; PARIS: Parkin interacting substrate; PD: Parkinson’s disease; PGC-1α: PPARγ coactivator-1 α.
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