Exaggerated mitophagy: a weapon of striatal destruction in the brain?

Abstract

Mechanisms responsible for neuronal vulnerability in the brain remain unclear. Striatal neurons are preferentially damaged by 3-nitropropionic acid (3-NP), a mitochondrial complex-II inhibitor, causing striatal damage reminiscent of Huntington's disease (HD), but the mechanisms of the selectivity are not as well understood. We have discovered that Rhes, a protein enriched in the striatum, removes mitochondria via the mitophagy process. The process becomes intensified in the presence of 3-NP, thereby eliminating most of the mitochondria from the striatum. We put forward the hypothesis that Rhes acts as a ‘mitophagy ligand' in the brain and promotes mitophagy via NIX, a mitophagy receptor. Since Rhes interacts and promotes toxicity in association with mutant huntingtin (mHTT), the genetic cause of HD, it is tempting to speculate on whether the exaggerated mitophagy may be a contributing factor to the striatal lesion found in HD. Thus, Rhes-mediated exaggerated mitophagy may act as a weapon of striatal destruction in the brain.

Mitochondrial Dysfunction and Mitophagy in Fuchs Endothelial Corneal Dystrophy

“…A protein enriched in the striatum called Rhes removes damaged mitochondria via mitophagy. The mitophagy intensifies in the presence of 3-NP, suggesting exaggerated mitophagy to be a contributing factor to Huntington's pathogenesis [52]. Similarly, Su et al showed that excessive mitophagy and autophagy contributes to chronic cerebral hypoperfusion-induced neuronal death, and its inhibition is valuable in preventing the disease [53].…”

“…However, excessive mitophagy might also be detrimental for the neurons in neurological diseases [52]. In Huntington's disease, striatal neurons are preferentially vulnerable to 3-nitropropionic acid (3-NP), a mitochondrial complex-II inhibitor.…”

Neuronal Mitophagy: Friend or Foe?

“…The tight coordination between mitochondrial biogenesis and degradation is essential for cellular, tissue and organismal physiology (Palikaras and Tavernarakis, 2014 ; Palikaras et al, 2015 ). Insufficient mitochondrial biogenesis and excessive mitophagy diminish mitochondrial population that burdens the remaining organelles, which subsequently promote mitophagy-mediated cell death ( Figure 2 ) (Palikaras and Tavernarakis, 2014 ; Subramaniam, 2020 ). Indeed, excessive mitochondrial elimination has been indicated as a cause of cell death in several disease models (Subramaniam, 2020 ).…”

“…Insufficient mitochondrial biogenesis and excessive mitophagy diminish mitochondrial population that burdens the remaining organelles, which subsequently promote mitophagy-mediated cell death ( Figure 2 ) (Palikaras and Tavernarakis, 2014 ; Subramaniam, 2020 ). Indeed, excessive mitochondrial elimination has been indicated as a cause of cell death in several disease models (Subramaniam, 2020 ). Notably, BNIP3-mediated mitophagy is shown to promote neuronal death both in vitro and in vivo upon ischemic stroke (Shi et al, 2014 ).…”

Mitophagy Regulates Neurodegenerative Diseases

“…Moreover, Rhes, a type of GTPase, was reported to upregulate mitophagy via the NIX receptor. This led to striatal cell death and striatal lesions, speculating that exaggerated mitophagy might be a contributing factor of HD [100,141]. Overall, abnormal mitochondrial size and morphology have been confirmed in HD, but the role of mitophagy (i.e., eliminating dysfunctional and unwanted mitochondria) remains controversial.…”