Mitochondria Localized microRNAs: An Unexplored miRNA Niche in Alzheimer's Disease and Aging

Mitochondria play several vital roles in the brain cells, especially in neurons to provide synaptic energy (ATP), Ca²⁺ homeostasis, Reactive Oxygen Species (ROS) production, apoptosis, mitophagy, axonal transport and neurotransmission. Mitochondrial dysfunction is a well-established phenomenon in the pathophysiology of many neurological diseases, including Alzheimer's disease (AD). Amyloid-beta (Aβ) and Phosphorylated tau (p-tau) proteins cause the severe mitochondrial defects in AD. A newly discovered cellular niche of microRNAs (miRNAs), so-called mitochondrial-miRNAs (mito-miRs), has recently been explored in mitochondrial functions, cellular processes and in a few human diseases. The mitochondria localized miRNAs regulate local mitochondrial genes expression and are significantly involved in the modulation of mitochondrial proteins, and thereby in controlling mitochondrial function. Thus, mitochondrial miRNAs are crucial to maintaining mitochondrial integrity and for normal mitochondrial homeostasis. Mitochondrial dysfunction is well established in AD pathogenesis, but unfortunately mitochondria miRNAs and their precise roles have not yet been investigated in AD. Therefore, an urgent need exists to examine and decipher the critical roles of mitochondrial miRNAs in AD and in the aging process. The current perspective sheds light on the latest insights and future research directions on investigating the contribution of mitochondrial miRNAs in AD and aging.