Mitochondria are maternally inherited semi-autonomous organelles that play a central role in redox
balance, energy metabolism, control of integrated stress responses, and cellular homeostasis. The molecular
communication between mitochondria and the nucleus is intricate and bidirectional in nature. Though mitochondrial
genome encodes for several key proteins involved in oxidative phosphorylation, several regulatory factors
encoded by nuclear DNA are prominent contributors to mitochondrial biogenesis and function. The loss of synergy
between this reciprocal control of anterograde (nuclear to mitochondrial) and retrograde (mitochondrial to
nuclear) signaling, triggers epigenomic imbalance and affects mitochondrial function and global gene expressions.
Recent expansions of our knowledge on mitochondrial epigenomics have offered novel perspectives for the
study of several non-communicable diseases including cancer. As mitochondria are considered beacons for pharmacological
interventions, new frontiers in targeted delivery approaches could provide opportunities for effective
disease management and cure through reversible epigenetic reprogramming. This review focuses on recent progress
in the area of mitochondrial-nuclear cross-talk and epigenetic regulation of mitochondrial DNA methylation,
mitochondrial micro RNAs, and post-translational modification of mitochondrial nucleoid-associated proteins
that hold major opportunities for targeted drug delivery and clinical translation.
Keywords: Mitochondrial targeting, mitochondrial medicine, mitochondrial-nuclear cross-talk, epigenomic signatures, translational research,
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