New Insights into Mitochondria in Health and Diseases

Abstract

Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell's survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson's disease, and cancer, as well as rare metabolic disorders, like Kearns-Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.

Keywords: ROS; aging; bioenergetics; mitochondrial; mitochondrial dysfunction; mitochondrial targeted therapy; mtDNA; mutations.

Figure 1

Mitochondrial structure and the process by which NADH + H⁺ enters the mitochondria via specific shuttling in the inner mitochondrial membrane. The process of producing ATP is intricate. For instance, the metabolism of glucose involves the cytoplasmic glycolysis process, the mitochondrial matrix TCA cycle, and oxidative phosphorylation accompanied by the production of ATP. Of these, the pyruvate transporter facilitates the entry of pyruvate generated during glycolysis into the mitochondria, but the mechanism of NADH + H+ entering the mitochondria is more intricate: 1. NADH + H⁺ in the cytoplasm is treated by malate dehydrogenase to make oxaloacetic acid (OAA) accept 2 H and become malic acid (MAL). 2. Malic acid enters mitochondria via transport carriers in the inner membrane.3. Under the action of malic acid entering mitochondria, NAD⁺ is used as acceptor to form oxaloacetic acid and NADH + H⁺. 4. Oxaloacetic acid and glutamic acid are transformed into aspartic acid and alpha-ketoglutaric acid by the interaction of glutamic acid with glutamic acid through glutamic oxaloacetic acid transaminase. 5. Aspartate (Asp) and α-ketoglutaric acid enter the cytoplasm with the help of mitochondrial transport carriers. 6. Glutamate (Glu) consumed in the mitochondria is supplemented by the exchange of glutamate in cellular fluid and outgoing aspartic acid through the reverse glutamate–aspartic acid transport carrier.

Figure 2

Mitophagy mediated by the PINK1–Parkin pathway during aging. PINK1 accumulates on the outer membrane of the mitochondria under depolarization or stress, and autophosphorylation activates it. In addition, the active PINK1 draws the cytoplasmic Parkin protein to the mitochondria and triggers Parkin’s E3 ubiquitin ligase activity by phosphorylating ubiquitin, which polyubiquitinates the protein found in the mitochondrial membrane. Specifically, signals for the identification of autophagy receptors are provided by ubiquitin chains connected by K63, and autophagy receptor proteins, like p62, OPTN, and NDP52, are attracted to mitochondria modified by ubiquitination to facilitate selective autophagy.

Figure 3

Complex regulatory networks in Parkinson’s disease. Parkinson’s disease has a complex etiology that includes both genetic and environmental influences. The three that will most likely impact mitochondrial function, cause abnormalities in mitochondrial electron transfer and oxidative phosphorylation, produce reactive oxygen species (ROS), and ultimately result in nerve cell death are oxidative stress, SNCA mutation, and LRRK2 mutation.