Mitochondria and Energetic Depression in Cell Pathophysiology

Abstract

Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting OPEN ACCESSInt. J. Mol. Sci. 2009, 10 2253 from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell's ability to do work and control the intracellular Ca 2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis.

V-ATPase is a candidate therapeutic target for Ewing sarcoma

“…Since Warburg's theory [3], it is now widely accepted that tumor cells drive a metabolic shift characterized by the suppression of OXPHOS combined with the activation of glycolysis as the main pathway for ATP synthesis [34]. In this study, we verified this metabolic alteration in ES, an extremely aggressive, poorly differentiated cancer of putative mesenchymal origin.…”

Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)

“…ATP depletion may cause ''cellular energy depression'' and consequent neuronal dysfunctions. By releasing cytochrome c, mitochondria may induce the apoptotic cell death program [99].…”

The Biarylpyrazole Compound AM251 Alters Mitochondrial Physiology via Proteolytic Degradation of ERRα

“…Mitotracker Green is a probe used to evaluate the mitochondrial mass and differentiate intact mitochondria from cellular debris while the measure of mitochondrial membrane potential, monitored by the fluorescence of mitochondrially loaded cationic potentiometric dye TMRM, serves to measure the electrical gradient across the mitochondria inner membrane established by electron transport chain activity (Seppet et al, 2009). Flow cytometric analyzes of Mitotracker Green and TMRM fluorescence profiles were performed in PANC-1 cells treated with AM251 (5 mM) and XCT790 (2.5 mM) for 16 hours (Fig.…”