Environ Mol Mutagen. 2010 Jun;51(5):391-405.
Mitochondrial dysfunction in neurodegenerative diseases and cancer.
de Moura MB, dos Santos LS, Van Houten B.
Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Abstract
Mitochondria are important integrators of cellular function and therefore affect the homeostatic balance of the cell.
Besides their important role in producing adenosine triphosphate through oxidative phosphorylation, mitochondria are involved in the control of cytosolic calcium concentration, metabolism of key cellular intermediates, and Fe/S cluster biogenesis and contributed to programmed cell death.
Mitochondria are also one of the major cellular producers of reactive oxygen species (ROS). Several human pathologies, including neurodegenerative diseases and cancer, are associated with mitochondrial dysfunction and increased ROS damage.
This article reviews how dysfunctional mitochondria contribute to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and several human cancers.
PMID: 20544881 [PubMed – indexed for MEDLINE]

DNA Repair (Amst). 2008 Jul 1;7(7):1110-20. Epub 2008 May 7.
Mitochondrial DNA damage and repair in neurodegenerative disorders.
Yang JL, Weissman L, Bohr VA, Mattson MP.
Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Abstract
By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons. Oxidative stress and damage to mitochondrial DNA during the aging process can impair mitochondrial energy metabolism and ion homeostasis in neurons, thereby rendering them vulnerable to degeneration.
Mitochondrial abnormalities have been documented in all of the major neurodegenerative disorders-Alzheimer’s, Parkinson’s and Huntington’s diseases, and amyotrophic lateral sclerosis.
Mitochondrial DNA damage and dysfunction may be downstream of primary disease processes such as accumulation of pathogenic proteins.
However, recent experimental evidence demonstrates that mitochondrial DNA damage responses play important roles in aging and in the pathogenesis of neurodegenerative diseases.
Therapeutic interventions that target mitochondrial regulatory systems have been shown effective in cell culture and animal models, but their efficacy in humans remains to be established.
PMID: 18463003 [PubMed – indexed for MEDLINE]PMCID: PMC2442166

Chem Res Toxicol. 2008 Jan;21(1):172-88. Epub 2007 Dec 4.
Oxidative stress and neurotoxicity.
Sayre LM, Perry G, Smith MA.
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA. LMS3@case.edu
Abstract
There is increasing awareness of the ubiquitous role of oxidative stress in neurodegenerative disease states. A continuing challenge is to be able to distinguish between oxidative changes that occur early in the disease from those that are secondary manifestations of neuronal degeneration. This perspective highlights the role of oxidative stress in Alzheimer’s, Parkinson’s, and Huntington’s diseases, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative and neuroinflammatory disorders where there is evidence for a primary contribution of oxidative stress in neuronal death, as opposed to other diseases where oxidative stress more likely plays a secondary or by-stander role. We begin with a brief review of the biochemistry of oxidative stress as it relates to mechanisms that lead to cell death, and why the central nervous system is particularly susceptible to such mechanisms. Following a review of oxidative stress involvement in individual disease states, some conclusions are provided as to what further research should hope to accomplish in the field.
PMID: 18052107 [PubMed – indexed for MEDLINE]

Curr Opin Cell Biol. 2009 Dec;21(6):894-9. Epub 2009 Sep 24.
Mitochondrial reactive oxygen species regulate hypoxic signaling.
Hamanaka RB, Chandel NS.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
Abstract
Physiological hypoxia results in a host of responses that include increased ventilation, constriction of the pulmonary artery, and a cellular transcriptional program that promotes glycolysis, angiogenesis, and erythropoiesis. Mitochondria are the primary consumers of cellular oxygen and have thus been speculated for years to be the site of cellular oxygen sensing. Many of the cellular responses to hypoxia are now known to be mediated by the production of reactive oxygen species at mitochondrial complex III. While the mechanism by which cytosolic oxidant concentration is increased during hypoxia is unknown, the importance of the maintenance of cellular oxygen supply requires further investigation into the role of ROS as hypoxia signaling molecules. The following is a brief overview of the current understanding of the role of mitochondrial-produced ROS in cellular oxygen signaling.
PMID: 19781926 [PubMed – indexed for MEDLINE]

Exp Physiol. 2006 Sep;91(5):807-19. Epub 2006 Jul 20.
Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia.
Guzy RD, Schumacker PT.
Department of Pediatrics, North-western University, Chicago, IL 60611, USA.
Abstract
All eukaryotic cells utilize oxidative phosphorylation to maintain their high-energy phosphate stores. Mitochondrial oxygen consumption is required for ATP generation, and cell survival is threatened when cells are deprived of O(2). Consequently, all cells have the ability to sense O(2), and to activate adaptive processes that will enhance the likelihood of survival in anticipation that oxygen availability might become limiting. Mitochondria have long been considered a likely site of oxygen sensing, and we propose that the electron transport chain acts as an O(2) sensor by releasing reactive oxygen species (ROS) in response to hypoxia. The ROS released during hypoxia act as signalling agents that trigger diverse functional responses, including activation of gene expression through the stabilization of the transcription factor hypoxia-inducible factor (HIF)-alpha. The primary site of ROS production during hypoxia appears to be complex III. The paradoxical increase in ROS production during hypoxia may be explained by an effect of O(2) within the mitochondrial inner membrane on: (a) the lifetime of the ubisemiquinone radical in complex III; (b) the relative release of mitochondrial ROS towards the matrix compartment versus the intermembrane space; or (c) the ability of O(2) to access the ubisemiquinone radical in complex III. In summary, the process of oxygen sensing is of fundamental importance in biology. An ability to control the oxygen sensing mechanism in cells, potentially using small molecules that do not disrupt oxygen consumption, would open valuable therapeutic avenues that could have a profound impact on a diverse range of diseases.
PMID: 16857720 [PubMed – indexed for MEDLINE

J Bioenerg Biomembr. 2009 Oct;41(5):433-40.
Role of mitochondrial-mediated signaling pathways in Alzheimer disease and hypoxia.
Carvalho C, Correia SC, Santos RX, Cardoso S, Moreira PI, Clark TA, Zhu X, Smith MA, Perry G.
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Abstract
Development of effective treatments for Alzheimer’s disease is complicated by the poor understanding of its pathophysiology. Recent work suggests mitochondria may play a primary role in neurodegeneration, due to alterations in mitochondria turnover and that the brain is specifically susceptible, due to high energy demand. Mitochondria are the major source of cellular energy through oxidative phosphorylation and regulate intracellular calcium levels and survival pathways. Hypoxia has been implicated in several neurodegenerative diseases including Alzheimer’s disease. During hypoxic events, mitochondrial complex III produces high levels of reactive oxygen species (ROS). These ROS seem to have a primary role in the regulation of the transcription factor hypoxia inducible factor 1alpha that triggers death effectors. Here we discuss the role of mitochondria in AD putting focus on the activation of hypoxia-mediated mitochondrial pathways, which could eventually lead to cell degeneration and death.
PMID: 19830532 [PubMed – indexed for MEDLINE

Curr Drug Targets. 2011 Jun;12(6):872-8.
Regulation of mitochondrial biogenesis in metabolic syndrome.
Rolo AP, Gomes AP, Palmeira CM.
Source
Center for Neurosciences and Cell Biology, Department of Life Sciences, University of Coimbra,
Portugal.
Abstract
Insulin resistant individuals manifest multiple disturbances in free fatty acids metabolism and have excessive lipid accumulation in insulin-target tissues. A wide range of evidence suggests that defective muscle mitochondrial metabolism, and subsequent impaired ability to oxidize fatty acids, may be a causative factor in the accumulation of intramuscular lipid and the development of insulin resistance. Such mitochondrial dysfunction includes loss of mitochondria, defects in the mitochondrial OXPHOS system and decreased rate of ATP synthesis. Stimulation of mitochondrial biogenesis appears as a strategy for the clinical management of the metabolic syndrome, by enhancing mitochondrial activity and protecting the cell against the increased flux of reduced substrates to the electron transport chain and thus reducing metabolic inflammation.
PMID:21269264[PubMed – indexed for MEDLINE]

Mediators Inflamm. 2013;2013:135698. doi: 10.1155/2013/135698. Epub 2013 Feb 28.
Mitochondrial dysfunction: a basic mechanism in inflammation-related non-communicable diseases and therapeutic opportunities.
Hernández-Aguilera A, Rull A, Rodríguez-Gallego E, Riera-Borrull M, Luciano-Mateo F, Camps J, Menéndez JA, Joven J.
Source
Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, carrer Sant Llorenç 21, 43201 Reus, Spain.
Abstract
Obesity is not necessarily a predisposing factor for disease. It is the handling of fat and/or excessive energy intake that encompasses the linkage of inflammation, oxidation, and metabolism to the deleterious effects associated with the continuous excess of food ingestion. The roles of cytokines and insulin resistance in excessive energy intake have been studied extensively. Tobacco use and obesity accompanied by an unhealthy diet and physical inactivity are the main factors that underlie noncommunicable diseases. The implication is that the management of energy or food intake, which is the main role of mitochondria, is involved in the most common diseases. In this study, we highlight the importance of mitochondrial dysfunction in the mutual relationships between causative conditions. Mitochondria are highly dynamic organelles that fuse and divide in response to environmental stimuli, developmental status, and energy requirements. These organelles act to supply the cell with ATP and to synthesise key molecules in the processes of inflammation, oxidation, and metabolism. Therefore, energy sensors and management effectors are determinants in the course and development of diseases. Regulating mitochondrial function may require a multifaceted approach that includes drugs and plant-derived phenolic compounds with antioxidant and anti-inflammatory activities that improve mitochondrial biogenesis and act to modulate the AMPK/mTOR pathway.
PMID:23533299[PubMed – indexed for MEDLINE] PMCID:PMC3603328