Finding the balance: The elusive mechanisms underlying auditory hair cell mitochondrial biogenesis and mitophagy

In all cell types, mitochondrial biogenesis is balanced with mitophagy to maintain a healthy mitochondrial pool that sustains specific energetic demands. Cell types that have a higher energetic burden, such as skeletal muscle cells and cardiomyocytes, will subsequently develop high mitochondrial volumes. In these cells, calcium influx during activity triggers cascades leading to activation of the co-transcriptional regulation factor PGC-1α, a master regulator of mitochondrial biogenesis, in a well-defined pathway. Despite the advantages in ATP production, high mitochondrial volumes might prove to be perilous, as it increases exposure to reactive oxygen species produced during oxidative phosphorylation. Mechanosensory hair cells are highly metabolically active cells, with high total mitochondrial volumes to meet that demand. However, the mechanisms leading to expansion and maintenance of the hair cell mitochondrial pool are not well defined. Calcium influx during mechanotransduction and synaptic transmission regulate hair cell mitochondria, leading to a possibility that similar to skeletal muscle and cardiomyocytes, intracellular calcium underlies the expansion of the hair cell mitochondrial volume. This review briefly summarizes the potential mechanisms underlying mitochondrial biogenesis in other cell types and in hair cells. We propose that hair cell mitochondrial biogenesis is primarily product of cellular differentiation rather than calcium influx, and that the hair cell high mitochondrial volume renders them more susceptible to reactive oxygen species increased by calcium flux than other cell types.