Production of mitochondrial ROS, mitochondrial ROS

Mitochondrial ROS (mtROS or mROS) are

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen ...

(ROS) that are produced by mitochondria. Generation of mitochondrial ROS mainly takes place at the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couple ...

located on the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. ...

during the process of

oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...

. Leakage of electrons at complex I and complex III from electron transport chains leads to partial reduction of oxygen to form

superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of ...

. Subsequently, superoxide is quickly dismutated to

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...

by two dismutases including superoxide dismutase 2 (SOD2) in

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ri ...

and superoxide dismutase 1 (SOD1) in mitochondrial intermembrane space. Collectively, both superoxide and hydrogen peroxide generated in this process are considered as mitochondrial ROS. Once thought as merely the by-products of cellular metabolism, mitochondrial ROS are increasingly viewed as important signaling molecules, whose levels of generation at 11 currently-identified sites vary depending on cellular energy supply and demand. At low levels, mitochondrial ROS are considered to be important for metabolic adaptation as seen in hypoxia. Mitochondrial ROS, stimulated by danger signals such as lysophosphatidylcholine and Toll-like receptor 4 and Toll-like receptor 2 bacterial ligands

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...

(LPS) and lipopeptides, are involved in regulating inflammatory response. Finally, high levels of mitochondrial ROS activate apoptosis/

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

pathways capable of inducing cell death.

COVID-19

Monocytes/macrophages are the most enriched immune cell types in the lungs of

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickl ...

patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α ( HIF1A) and consequently promotes glycolysis. HIF1A-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting mitochondrial ROS may have great therapeutic potential for the development of novel drugs to treat patients with coronavirus.

Aging

Mitochondrial ROS can promote cellular

senescence Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...

and

aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological prop ...

s in the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...

of mice. Ordinarily mitochondrial

SOD2 Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the ''SOD2'' gene on chromosome 6. A related pseudogene has been identified on chromosome 1 ...

protects against mitochondrial ROS. Epidermal cells in mutant mice with a genetic SOD2 deficiency undergo cellular senescence, nuclear

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

, and irreversible arrest of proliferation in a portion of their

keratinocyte Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referred ...

s. Mutant mice with a conditional deficiency for mitochondrial SOD2 in

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tissue ...

have an accelerated aging

. This aging phenotype includes weight loss, skin

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply ...

, kyphosis (curvature of the spine), osteoporosis,

muscle degeneration Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

and reduced life span.

DNA damage

Mitochondrial ROS attack DNA readily, generating a variety of DNA damages such as oxidized bases and strand breaks. The major mechanism that cells use to repair oxidized bases such as 8-hydroxyguanine, formamidopyrimidine and 5-hydroxyuracil is

base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...

(BER). BER occurs in both the cell nucleus and in mitochondria.

References

{{Reflist Free radicals Mitochondria Oxygen