Mitochondria in health and disease: cellular powerhouses, signaling centers, and drivers of dysfunction

Abstract

Although the mitochondria are known as the cellular powerhouse, their function is beyond energy generation. These organelles regulate cellular metabolism, yet maintains a tightly regulated reactive oxygen species (ROS) generation and optimal redox state. In addition, mitochondria serve as mediators of physiological and pathological processes, such as maintenance of calcium balance, and control of apoptosis and mitophagy. All these make the mitochondria a major factor in both cellular and organismal regulation. However, mitochondria dysfunction may occur through many processes, including genetic mutations, increased production of ROS, metabolic failure from impaired electron transport chain activity, and dysregulated dynamics or mitophagy. Several self-perpetuating damages accumulate from these processes and influence clinical pathologies, such as aging, metabolic syndrome, cancer, neurodegeneration, and reproductive disorders. Recent studies demonstrate promising therapeutic targets for mitochondrial dysfunction. Examples include targeted antioxidants, such as MitoQ and SkQ1, to selectively neutralize mitochondrial ROS, pharmacological modulators to enhance mitochondrial biogenesis and to restore NAD+ homeostasis via PGC-1α activation, gene-editing technologies, such as mitoTALENs and mtZFNs to selectively eliminate pathogenic mitochondrial DNA mutations, and mitochondrial transplantation as a new technique to replace damaged organelles. Together, these novel approaches highlight the need for research in mitochondrial function to change the therapeutic landscape in the management of mitochondrial dysfunction-associated diseases.