Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back and death. Finally, the relative benefits of suppressing mitochondrial fusion vs. enhancing mitochondrial fusion in ALS are speculated upon, and the paper concludes with the prediction that the two approaches could be additive or synergistic, although a side-by-side comparative trial may be challenging to perform.

Automated summary

This article discusses the role of mitochondrial abnormalities in the progression of amyotrophic lateral sclerosis (ALS) and explores the potential of regulating mitochondrial function to delay ALS. Experimental evidence suggests that abnormal mitochondrial fusion, fission, and transport are closely related to the pathogenesis of ALS. Moreover, it has been found that normalizing mitochondrial function can delay the development of ALS. Finally, the relative benefits of suppressing mitochondrial fusion and enhancing mitochondrial fusion in the treatment of ALS are speculated upon.