Mitochondrial metabolism is a well-established factor in many different diseases. Specifically, neurodegenerative diseases, cancer, cardiovascular disease, and aging are all thought to be initiated or propagated in part through mitochondrial dysfunction. This association affords the opportunity to interrogate cellular processes specific to mitochondria in hopes of further characterizing pathological factors. Of note, the mitochondrial matrix is the primary cellular site of oxidative metabolism. As a result oxidative has received significant attention as playing an important role in these diseases.
Although commonly attributed to oxidative insults, the underlying pathology could result in part from perturbed mitochondrial metabolic processes. This means that there is a continuing need to further our understanding of the relationship between mitochondrial metabolism and disease pathogenesis. By expanding our understanding of the metabolic adaptations arising from disrupted mitochondrial metabolism, we are likely to shed light on unknown factors that may play a role in the development of a wide range of diseases. Specifically, this approach will likely offer a synergistic approach with conventional antioxidant approaches to disease prevention.
Mitochondria are cellular organelles that serve as the main site of ATP production. Given this important role in sustaining energy-dependent functions, mitochondria are often referred to as the “powerhouse” of the cell. The processes by which ATP is produced are complex, involving an intricate network of metabolic pathways that is adaptable to different sources of carbon. Glucose, glutamine, and fatty acids are among the major carbon-providing nutrients, which are ultimately shuttled to the mitochondrial matrix to sustain the required energy production. The catabolic processing of these nutrients and others like them result in the production of reducing equivalents, primarily NADH and FADH2. The electrons derived from these reduced cofactors are subsequently shuttled down a series of electron transferring protein complexes, which, as a whole, make up the electron transport chain (ETC). In aerobic respiration, this process ultimately leads to the reduction of oxygen, forming water. Importantly, the energy released throughout this process is converted into an electrochemical gradient across the inner-mitochondrial membrane. This gradient is utilized for mitochondrial ATP synthesis. This entire process is known as oxidative phosphorylation or OX-PHOS and is essential to sustaining the vast majority of life as we know it.
The metabolic metabolism by which NADH and FADH2 can be produced are numerous but intricately connected. As a result, cellular metabolic pathways are often depicted as an intertwined roadmap. The diversity and complicated nature of the catabolic processing of these nutrients is balanced by the evolutionarily conserved ubiquitous requirement of Coenzyme A (CoA) as an activated acyl-carrier. Derived from the vitamin B5 pantothenic acid, CoA thioesters act as acyl-carriers of activated carboxylic acids. Vitamin B5 is an essential nutrient to mammals, but can be synthesized from precursors in lower organisms, thus emphasizing the importance of this carrier to biochemical processes. Produced from the condensation of carboxylic acids with free thiol groups such as the one present on free CoA (CoASH), thioester bonds have inherently high bond energies, making them relatively unstable. This high potential energy facilitates the transfer of the acyl group from acyl-CoA species to substrates, making it an energetically favorable process. For example, protein acetylation is an important regulatory post-translational modification and is understood to be dependent almost entirely on acetyl-CoA as a substrate as opposed to free acetate. In addition to protein modifications, acyl-CoAs are ubiquitous in cellular metabolism and are directly utilized by metabolic enzymes.
Mitochondrial dysfunction is clearly associated with a wide range of diseases. In particular, neurodegenerative diseases with characteristic protein aggregates such as Alzheimer’s and Parkinson’s disease (PD) have received extensive attention and seem to be initiated in part by mitochondrial dysfunction. Furthermore, oxidative damage has been implicated as a prerequisite to the formation of these aggregates. For this reason great effort has been placed on understanding the role of mitochondrial oxidative damage leading to cell death. The highly oxidative environment of the mitochondrial matrix and the electron transferring components of the ETC make it a leading intracellular site of reactive oxygen species (ROS) generation. Impairment of the ETC and related components are known to increase the production of ROS which can be harmful to the cell if they overrun endogenous protective antioxidant responses.