https://tspace.library.utoronto.ca/bitstream/1807/34929/3/Skrtic_Marko_201211_PhD_thesis.pdf

Inhibition of Mitochondrial Translation as a Therapeutic Strategy for Human Acute Myeloid Leukemia

Stroke and circulatory arrest cause interferences in blood flow to the brain that result in considerable tissue damage. The primary method to reduce or prevent neurologic damage to patients suffering from brain ischemia is prompt restoration of blood flow to the ischemic tissue. However, paradoxically, restoration of blood flow causes additional damage and exacerbates neurocognitive deficits among patients who suffer a brain ischemic event. Mitochondria play a critical role in reperfusion injury by producing excessive reactive oxygen species (ROS) thereby damaging cellular components, and initiating cell death. In this review, we summarize our current understanding of the mechanisms of mitochondrial ROS generation during reperfusion, and specifically, the role the mitochondrial membrane potential plays in the pathology of cerebral ischemia/reperfusion. Additionally, we propose a temporal model of ROS generation in which posttranslational modifications of key oxidative phosphorylation (OxPhos) proteins caused by ischemia induce a hyperactive state upon reintroduction of oxygen. Hyperactive OxPhos generates high mitochondrial membrane potentials, a condition known to generate excessive ROS. Such a state would lead to a “burst” of ROS upon reperfusion, thereby causing structural and functional damage to the mitochondria and inducing cell death signaling that eventually culminate in tissue damage. Finally, we propose that strategies aimed at modulating this maladaptive hyperpolarization of the mitochondrial membrane potential may be a novel therapeutic intervention and present specific studies demonstrating the cytoprotective effect of this treatment modality.

/pdf/molecular-mechanisms-of-ischemia-reperfusion-injury-in-brain-41y4spq2z6.pdf

Molecular Mechanisms of Ischemia–Reperfusion Injury in Brain: Pivotal Role of the Mitochondrial Membrane Potential in Reactive Oxygen Species Generation

The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB(1)) is present at the membranes of mouse neuronal mitochondria (mtCB(1)), where it directly controls cellular respiration and energy production. Through activation of mtCB(1) receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB(1) receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus. Thus, mtCB(1) receptors directly modulate neuronal energy metabolism, revealing a new mechanism of action of G protein-coupled receptor signaling in the brain.

/pdf/mitochondrial-cb1-receptors-regulate-neuronal-energy-3meqs6503g.pdf

Mitochondrial CB1 receptors regulate neuronal energy metabolism

The mitochondrial respiratory chain is a major source of reactive oxygen species (ROS) in eukaryotic cells. Mitochondrial ROS production associated with a dysfunction of respiratory chain complexes has been implicated in a number of degenerative diseases and biological aging. Recent findings suggest that mitochondrial ROS can be integral components of cellular signal transduction as well. Within the respiratory chain, complexes I (NADH:ubiquinone oxidoreductase) and III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc 1 complex) are generally considered as the main producers of superoxide anions that are released into the mitochondrial matrix and the intermembrane space, respectively. The primary function of both respiratory chain complexes is to employ energy supplied by redox reactions to drive the vectorial transfer of protons into the mitochondrial intermembrane space. This process involves a set of distinct electron carriers designed to minimize the unwanted leak of electrons from reduced cofactors onto molecular oxygen and hence ROS generation under normal circumstances. Nevertheless, it seems plausible that superoxide is derived from intermediates of the normal catalytic cycles of complexes I and III. Therefore, a detailed understanding of the molecular mechanisms driving these enzymes is required to understand mitochondrial ROS production during oxidative stress and redox signalling. This review summarizes recent findings on the chemistry and control of the reactions within respiratory complexes I and III that result in increased superoxide generation. Regulatory contributions of other components of the respiratory chain, especially complex II (succinate:ubiquinone oxidoreductase) and the redox state of the ubiquinone pool (Q-pool) will be briefly discussed.

Molecular Mechanisms of Superoxide Production by the Mitochondrial Respiratory Chain

Most reactive oxygen species (ROS) are generated in cells by the mitochondrial respiratory chain. Mitochondrial ROS production is modulated largely by the rate of electron flow through respiratory chain complexes. Recently, it has become clear that under hypoxic conditions, the mitochondrial respiratory chain also produces nitric oxide (NO), which can generate other reactive nitrogen species (RNS). Although excess ROS and RNS can lead to oxidative and nitrosative stress, moderate to low levels of both function in cellular signaling pathways. Especially important are the roles of these mitochondrially generated free radicals in hypoxic signaling pathways, which have important implications for cancer, inflammation and a variety of other diseases.

https://www.cell.com/trends/endocrinology-metabolism/pdf/S1043-2760(09)00088-5.pdf

Mitochondrial generation of free radicals and hypoxic signaling

Regulation of mitochondrial respiration and apoptosis through cell signaling: Cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation

New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms.

Phosphorylation and Kinetics of Mammalian Cytochrome c Oxidase

https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(09)00046-X.pdf

Rabia Ramzan

Papers

Regulation of mitochondrial respiration and apoptosis through cell signaling: Cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation

New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms.

Phosphorylation and Kinetics of Mammalian Cytochrome c Oxidase

Degenerative diseases, oxidative stress and cytochrome c oxidase function

The role of mitochondrial membrane potential in ischemic heart failure.