Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

Abstract

In the developing and mature brain, mitochondria act as central hubs for distinct but interwined pathways, necessary for neural development, survival, activity, connectivity and plasticity. In neurons, mitochondria assume diverse functions, such as energy production in the form of ATP, calcium buffering and generation of reactive oxygen species. Mitochondrial dysfunction contributes to a range of neurodevelopmental and neurodegenerative diseases, making mitochondria a potential target for pharmacological-based therapies. Pathogenesis associated with these diseases is accompanied by an increase in mitochondrial mass, a quantitative increase to overcome a qualitative deficiency due to mutated mitochondrial proteins that are either nuclear- or mitochondrial-encoded. This compensatory biological response is maladaptive, as it fails to sufficiently augment the bioenergetically functional mitochondrial mass and correct for the ATP deficit. Since regulation of neuronal mitochondrial biogenesis has been scantily investigated, our current understanding on the network of transcriptional regulators, co-activators and signaling regulators mainly derives from other cellular systems. The purpose of this review is to present the current state of our knowledge and understanding of the transcriptional and signaling cascades controlling neuronal mitochondrial biogenesis and the various therapeutic approaches to enhance the functional mitochondrial mass in the context of neurodevelopmental disorders and adult-onset neurodegenerative diseases.

Novel subcellular localization of the DNA helicase Twinkle at the kinetochore complex during mitosis in neuronal-like progenitor cells

“…PC12-ND6 cells behave as neuronal progenitor cells poised to withdraw from cell cycle and undergo terminal differentiation upon neurotrophic cues (Uittenbogaard and Chiaramello, 2004; 2005; Uittenbogaard et al 2010), thereby mimicking the proliferation potential of NeuroD6 + committed neural progenitors during neurogenesis (Wu et al 2005). Moreover, NeuroD6 coordinates neuronal differentiation with mitochondrial biogenesis to provide sufficient mitochondrial mass for proper neurite outgrowth (Baxter et al 2009; Uittenbogaard et al 2012; Uittenbogaard and Chiaramello, 2014). …”

Sitagliptin promotes mitochondrial biogenesis in human SH‐SY5Y cells by increasing the expression of PGC‐1α/NRF1/TFAM

“…Mitochondria have been identified as ubiquitous organelles distributed in all kinds of cells in mammalians. Mitochondria act as powerhouses that are responsible for energy supply via generating ATP in the brain . Mitochondrial dysfunction in the brain has been associated with the pathogenesis of several types of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease .…”

Editorial (Thematic Issue: Mitochondrial Biogenesis: Pharmacological Approaches)

“…In the context of neural differentiation, Martine Uittenbogaard and Anne Chiaramello (Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, USA) [7] thoroughly describe the implication of mitochondrial biogenesis on neuronal differentiation, its timing, its regulation by specific signaling pathways and new potential therapeutic strategies. The maintenance of mitochondrial homeostasis is crucial for neuronal development.…”