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Review
. 2013 Sep:62:37-46.
doi: 10.1016/j.freeradbiomed.2013.04.016. Epub 2013 Apr 19.

PGC-1α, mitochondrial dysfunction, and Huntington's disease

Ashu Johri  1 , Abhishek Chandra  2 , M Flint Beal  2
Affiliations
Review

PGC-1α, mitochondrial dysfunction, and Huntington's disease

Ashu Johri et al. Free Radic Biol Med. 2013 Sep.

Abstract

The constant high energy demand of neurons makes them rely heavily on their mitochondria. Dysfunction of mitochondrial energy metabolism leads to reduced ATP production, impaired calcium buffering, and generation of reactive oxygen species. There is strong evidence that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Huntington's disease (HD). Studies over the past few years have implicated an impaired function of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), a transcriptional master coregulator of mitochondrial biogenesis, metabolism, and antioxidant defenses, in causing mitochondrial dysfunction in HD. Here we have attempted to discuss in a nutshell, the key findings on the role of PGC-1α in mitochondrial dysfunction in HD and its potential as a therapeutic target to cure HD.

Keywords: 3-NP; 3-nitropropionic acid; 4-hydroxynonenal; 8-OHdG; 8-hydroxy-2′-deoxyguanosine; BAT; Energy metabolism; HD; HNE; Huntington's disease; MBP; MDA; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; NOXNADPH; Neurodegeneration; OXPHOS; Oxidative stress; PGC-1α; PPAR; PPARs; ROS; SIRT1; SIRT3; Therapeutics; brown adipose tissue; malondialdehyde; myelin basic protein; oxidase; oxidative phosphorylation; peroxisome proliferator-activated receptor; peroxisome proliferator-activated receptor-γ coactivator-1α; reactive oxygen species.

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Figures

Figure 1
Figure 1
Mutant huntingtin (mHtt) causes mitochondrial dysfunction in HD by multiple mechanisms. Mutant huntingtin: (1) binds to PGC-1α promoter reducing its expression; (2) binds to PGC-1α directly reducing its activity, which in turn results in reduced expression of PGC-1α target genes such as those involved in mitochondrial biogenesis and antioxidant defense; (3) binds to DRP1 more tightly than the wild-type protein, tripping the balance of mitochondrial fission-fusion processes in favor of fission; and (4) interferes with axonal transport of mitochondria. The net result of these impairments is low ATP at nerve terminals which culminates into neuronal death.
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