Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.

Keywords: amyotrophic lateral sclerosis; epigenetics; mitochondria; neural stem cells; neurogenesis.

FIGURE 1

The postulated role of mitochondrial function in neurogenesis. Mitochondrial function is crucial not only for the survival and proliferation of neural stem cells (NSCs; designated as stem cells for simplicity purposes) (1), but also for the proliferation of progenitor and precursor cells (1), and the differentiation (2) and migration (3) of newly generated neurons. Indeed all of the steps in the neurogenic process are energy dependent, thus relying on intact mitochondrial function.

FIGURE 2

Mitochondrial function and epigenetic modulation as putative regulators of neurogenesis and neuronal survival. Functional mitochondria allow normal brain metabolism and development due to the maintenance of an endogenous neural stem cell pool and supporting the mechanisms of adult neurogenesis. Changes in mitochondrial function result in altered mitochondrial metabolism, dynamics, and transport, as well as generation of reactive oxygen species (ROS) and oxidative stress, and these disturbances can then culminate in the impairment of stem cell self-renewal, a decrease in adult neurogenesis, and neuronal death. Conversely, epigenetic modulation can promote mitochondrial metabolism, thus potentially reestablishing normal levels of adult neurogenesis while also promoting neuronal survival and preventing neuronal death.