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.
Keywords: Mitochondrial DNA maintenance, adaptive mitochondrial biogenesis, mitochondrial fusion-fission, mitophagy, maternally inherited
mitochondrial diseases, Parkinson’s disease, Huntington’s disease, small-molecule-based therapies.
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