Mitochondria: It is all about energy

Abstract

Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.

Keywords: hormesis; mitochondria; mitochondrial dysfunction; mitochondrial hormesis; mitochondrial metabolism.

FIGURE 1

Mitochondrial functions: a visual representation of the functions of mitochondria discussed in this paper. Right: within the cell, mitochondria are anchored and transported across the cytoskeleton and cell membranes. Mitochondrial density is especially high at the perinuclear level and near the endoplasmic reticulum in most cells (also in the synaptic areas of neurons). The physical interactions of the structural domains known as mitochondria-associated membranes (MAMs) are physical contacts between organelles, such as the nucleus, lysosomes, endoplasmic reticulum, Golgi apparatus, that regulate messages through the transfer of ions and metabolites that act as a signaling center. This regulates the demands of substrate ATP and reactive oxygen species (ROS), among others. Left: intercellular communication. Cell-free mitochondria and their probable signaling functions.

FIGURE 2

Warburg effect and anti-Warburg effect. Switch From OXPHOS to aerobic glycolysis. Warburg effect and anti-Warburg effect. Under physiological conditions, cells can change from mitochondrial respiration to cytosolic respiration. Mitochondria allow the efficient production of ATP and regulate temperature, producing ROS (OXPHOS). In the presence of nutrients, cytosolic glycolysis permits cell repair/proliferation without oxidation, which facilitates the production of amino acids, fats, and nucleotides, among others. It is important to keep these processes alternate and intermittent. Right: in pathological states, some risk factors are mentioned, such as inflammation, loneliness, glucose surplus, and some medications, which induce a metabolic change from OXPHOS to aerobic glycolysis directed by the mechanistic target of rapamycin if persistently maintained (mTORC1/mTORC2). Both continously activated result in failure of the lysosomal and autophagy mechanisms inducing persistent anabolic state, fibrosis, excess proliferation, and changes in the immunometabolic phenotype that could result in CNCDs. Left: to restore physiological states and recover OXPHOS, exercise and fasting achieve an anti-Warburg effect. During nutrient deprivation, cells demand OXPHOS to increase bioenergetic capacity by driving a decrease in fission and remodeling in the electron transport chain (ETC) or cristae morphology. It is not yet clear, but probably, ETC architecture remodeling is driven because of endoplasmic reticulum ER stress during fasting because of the disruption of protein folding and glycosylation. An imbalance in protein folding capacity starts the unfolded protein response (UPR) mechanism, activating transcription factor (ATF6/ATF4), protein kinase R- (PKR-) like ER kinase (PERK), and inositol-requiring enzyme (IRE1) to re-establish ER homeostasis and maintain protein folding. Physical contact sites termed mitochondria-ER-associated membranes (MAMs) regulate calcium homeostasis, mitochondrial fission, lipid metabolism, autophagy, and inflammasome activity. ER communicates with the OXPHOS system to increase ATP supply and promote protein homeostasis. Exercise also induced mitochondrial cristae remodeling or shaping, improving the activity of respiratory chain complexes (CI, CII, CIII, and CIV) in the inner membrane and mitochondrial respiratory efficiency. Exercise impacts the stoichiometry of the SCs, enhancing the efficiency of electron flux by segmentation of the CoQ, improving the stability of the individual respiratory complexes, and avoiding ROS excess.

FIGURE 3

mTOR pathway: mTORC1 promotes protein synthesis by phosphorylating eukaryotic initiation factor 4E-binding proteins (4E-BPs) and p70 S6 kinase 1 (S6K1), increasing the production of ATP, nucleotides, and lipids. The lipid synthesis occurs primarily through the sterol regulatory element, protein-binding protein ½ (SREBP1/2), and peroxisome proliferator-activated receptor-γ (PPARγ). In the absence of sterols, SREBPs translocate to the nucleus to regulate genes for de novo cholesterol and other lipid synthesis. mTOR1 regulates the supply of one-carbon units for the biosynthesis of nucleotides for DNA/RNA replication, as it regulates methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), the mitochondrial tetrahydrofolate cycle enzyme, carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarboxylase (ATCase), dihydroorotase (CAD), and the rate-limiting enzyme in pyrimidine biosynthesis, among others. mTORC1 regulates the transcription factor hypoxia-inducible factor 1α (HIF1α), which increases the expression of glycolytic enzymes and favors glycolysis over OXPHOS. mTORC1 activates mitochondrial transcripts through 4E-BP1 and stimulates mitochondrial biogenesis by driving PGC1α. mTORC1 can simultaneously activate SREBPs, transcription factor ATF4, HIF1, Yin Yang 1 (YY1), PPARy, and PGC1a to drive mitochondrial regulation, ATP regulation, macromolecules synthesis, and cellular growth, blocking lysosomal biogenesis through transcription factor EB (TFEB). mTORC2 effectors include protein kinase B (Akt/PKB) and protein kinase C alpha (PKCα), a member of the AGC family of protein kinases (PKA/PKG/PKC). mTOR2 plays a role in cytoskeletal rearrangement, actin regulation, chemotaxis, migration, and cell survival. Akt is a central early effector in the phosphatidylinositol 3-kinase-protein kinase B (PI3K) pathway, where it mediates the cellular response to insulin and promotes proliferation. Akt regulates metabolism to resist stressors through the transcription factors of FOXO1/3a and NAD kinase. In addition, Akt can mediate between mTORC1 and mTORC2 complexes by inactivating tuberous sclerosis complex 2 (TSC2), a strong inhibitor of mTORC1 activity.

FIGURE 4

Visual representation of proposed strategies improving mitochondrial health: hormesis refers to the evolutionarily conserved adaptive responses of all living organisms to acute/temporary environmental mild physiological stress, nutritional or even voluntary challenges, through which the system modifies its tolerance to more dangerous stressors. Lifestyle interventions based on this principle are also known as hormetic strategies. At the mitochondrial level: mitohormetic strategies. Mitohormesis could support mitochondrial resilience and health, especially preventing CNCDs or premature and failed aging.