Targeting mitochondrial bioenergetics as a promising therapeutic strategy in metabolic and neurodegenerative diseases

Abstract

Mitochondria are the organelles that generate energy for the cells and act as biosynthetic and bioenergetic factories, vital for normal cell functioning and human health. Mitochondrial bioenergetics is considered an important measure to assess the pathogenesis of various diseases. Dysfunctional mitochondria affect or cause several conditions involving the most energy-intensive organs, including the brain, muscles, heart, and liver. This dysfunction may be attributed to an alteration in mitochondrial enzymes, increased oxidative stress, impairment of electron transport chain and oxidative phosphorylation, or mutations in mitochondrial DNA that leads to the pathophysiology of various pathological conditions, including neurological and metabolic disorders. The drugs or compounds targeting mitochondria are considered more effective and safer for treating these diseases. In this review, we make an effort to concise the available literature on mitochondrial bioenergetics in various conditions and the therapeutic potential of various drugs/compounds targeting mitochondrial bioenergetics in metabolic and neurodegenerative diseases.

Keywords: Antioxidants; Bioenergetics; Electron transport chain; Mitochondrial dysfunction; Oxidative stress.

Fig. 1

Process of mitochondrial fission and fusion in cells. The mitochondrial fusion and fission are regulated by guanosine triphosphatases (GTPases) of dynamin family. The fusion is conducted by mitofusin 1 and 2 (MFN1 and MFN2) and optic atrophy 1 (OPA1) proteins, while Fission 1 (FIS1) and Dynamin-related protein 1 (DRP1) help in the regulation of fission. The mitofusins (Mfn1 and Mfn2) mediate the fusion of outer membranes, and OPA1 mediates the fusion of inner membranes of a mitochondrion, which results in an elongated mitochondrion DRP1 is transported from cytosol to the outer mitochondrial membrane, making an assembly on the surface which results in separation of the organelle into two.

Fig. 2

Mitochondrial abnormalities leading to altered bioenergetics and disease pathology. Abnormalities in mitochondria can lead to abnormal bioenergetics followed by disease. An imbalance between mitochondrial fusion and fission can cause detrimental bioenergetics. Inflammation of mitochondria due to osmotic imbalance between the matrix and cytosol may affect ATP production and lead to various diseases.

Fig. 3

Mitochondria as a source of ATP production and reactive oxygen species (ROS). The figure shows the electron transport chain present in the inner mitochondrial membrane and the process of ATP synthesis and production of ROS as a byproduct. The complexes (I-IV) transfer electrons and reach oxygen, the final electron acceptor. This flow of electrons also pumps protons out of the matrix concomitantly, creating an electrochemical gradient that helps synthesise ATP from ADP and inorganic phosphate (Pi). The ROS such as ONOO- and ^•OH generated due to leak of electrons can lead to oxidative damage and mitochondrial dysfunction, which play a central role in the pathogenesis of many diseases.