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PubMed2002

Mitochondria as a pharmacological target.

Mitochondria play a central role in energy metabolism within the cell. Mitochondrial dysfunctions lead to various neurodegenerative disorders and to the so-called "mitochondrial diseases". A vast amount of evidence points to the implication of mitochondria in such complex processes as apoptosis and cardioprotection. The purpose of this review is to present a recent state of our knowledge and understanding of the action of various therapeutically applied substances on mitochondria. These include antitumor, immunosuppressant, and antiviral drugs, potassium channel openers, sulfonylureas, and anesthetics. Some of these substances are specifically designed to affect mitochondrial functions. In other cases, drugs with primary targets in other cellular locations may modify mitochondrial functions as side effects. In any case, identification of mitochondria as primary or secondary targets of a drug may help us to better understand the drug's mechanism of action and open new perspectives for its application. As far as possible, the molecular mechanisms of the interference of particular drugs in the mitochondrial metabolism will be described. In some cases, metabolic routes in which the drugs interfere will also be briefly outlined.

Animals↗
PubMed2007

Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis.

Increased lung cell apoptosis and necrosis occur in patients with chronic obstructive pulmonary disease (COPD). Mitochondria are crucially involved in the regulation of these cell death processes. Cigarette smoke is the main risk factor for development of COPD. We hypothesized that cigarette smoke disturbs mitochondrial function, thereby decreasing the capacity of mitochondria for ATP synthesis, leading to cellular necrosis. This hypothesis was tested in both human bronchial epithelial cells and isolated mitochondria. Cigarette smoke extract exposure resulted in a dose-dependent inhibition of complex I and II activities. This inhibition was accompanied by decreases in mitochondrial membrane potential, mitochondrial oxygen consumption, and production of ATP. Cigarette smoke extract abolished the staurosporin-induced caspase-3 and -7 activities and induced a switch from epithelial cell apoptosis into necrosis. Cigarette smoke induced mitochondrial dysfunction, with compounds of cigarette smoke acting as blocking agents of the mitochondrial respiratory chain; loss of ATP generation leading to cellular necrosis instead of apoptosis is a new pathophysiological concept of COPD development.

Cells, Cultured↗
PubMed2026

TIGAR deficiency enhances cardiac resilience through epigenetic programming of Parkin expression.

Mitochondrial dysfunction devastates the heart in major cardiovascular diseases, yet the mechanisms governing mitochondrial quality control remain elusive. We discovered that TIGAR (TP53-induced glycolysis and apoptosis regulator) deficiency established profound cardiac protection through developmental epigenetic programming of Parkin expression. Using mice with whole-body and cardiomyocyte-specific TIGAR knockout, we demonstrated remarkable cardioprotection following myocardial infarction with maintained ejection fraction, and complete resistance to diet-induced cardiac hypertrophy despite comparable weight gain. TIGAR deficiency triggered dramatic increases in Parkin expression across all somatic tissues except testes, where Parkin levels remained extraordinarily high (100-fold greater than cardiac levels) regardless of TIGAR status, revealing tissue-specific regulatory mechanisms. This protection was entirely Parkin dependent, as double-knockout mice lost all cardioprotective benefits. Crucially, adult TIGAR manipulation failed to alter Parkin levels, demonstrating that this pathway operated exclusively during critical developmental windows to program lifelong cardiac resilience. Whole-genome bisulfite sequencing identified reduced DNA methylation in Prkn intron 10 as the key regulatory mechanism, with CRISPR deletion dramatically increasing Parkin expression in multiple cell lines. Our findings reveal how early cardiac metabolism programs lifelong cardiac function through epigenetic mechanisms, and identify developmental metabolic programming as a potential therapeutic target for preventing both ischemic heart disease and metabolic cardiomyopathy.

Animals↗
PubMed1998

Genetic epidemiology of Parkinson's disease.

The cause of Parkinson's disease (PD) is unknown. The major risk factors identified to date are family history, age, and elements of rural living. Nearly one-third of all PD cases are familial, a small subset of which appears autosomal dominant; however, the majority exhibit no clear inheritance pattern. Autosomal dominant PD is genetically heterogeneous: two PD genes have been mapped to chromosomes 2 and 4 and there may be additional as yet unidentified genes. The common forms of PD-both familial and sporadic cases-appear to involve a complex interplay of genetic susceptibility and environmental exposure. The observations that rural residence and pesticide exposure increase the risk of developing PD, and that a synthetic drug, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, can cause parkinsonism, suggest that at least a subset of PD may be caused by a toxin. Furthermore, modest but significant associations have been reported between PD susceptibility and genes that regulate metabolism of drugs and neurotoxins. There is also evidence for mitochondrial dysfunction in PD, a finding that was recently traced to anomalies in mitochondrial DNA. At the present time, the genetics of PD appear to be complex, involving multiple nuclear genes and possibly mitochondrial genes as well.

Aged↗
PubMed2006

Minireview: implication of mitochondria in insulin secretion and action.

Mitochondria are essential for intermediary metabolism as well as energy production in the cell. Their aerobic metabolism permits oxidation of glucose and fatty acids for the generation of ATP and other intermediates that are exchanged with the cytoplasm for various biosynthetic and secretory processes. In the pancreatic beta-cell, glucose carbons are quantitatively funneled to the mitochondria, where signals for the initiation and potentiation of insulin secretion are generated. After mitochondrial activation, the plasma membrane is depolarized with ensuing cytosolic calcium transients and exocytosis of insulin. Calcium also acts in a feed-forward manner on mitochondrial metabolism, which contributes to sustained second phase insulin secretion. Patients with mitochondrial diabetes and a corresponding mouse model display defective glucose-stimulated insulin secretion and reduced beta-cell mass, leading to overt diabetes. Normal mitochondrial activity appears to be equally important in the action of insulin on its target tissues. The development of insulin resistance may involve impairment of glucose oxidation after short exposure to increased levels of circulating free fatty acids. Insulin resistance in the elderly and in relatives of type 2 diabetic patients has also been associated with mitochondrial dysfunction. Both prevention and treatment of type 2 diabetes should focus on mitochondrial targets for the improvement of nutrient-stimulated insulin secretion and their utilization in peripheral tissues.

Adenosine Triphosphate↗
PubMed1998

Creation and characterization of a mitochondrial DNA-depleted pancreatic beta-cell line: impaired insulin secretion induced by glucose, leucine, and sulfonylureas.

It has been proposed that mitochondrial oxidative phosphorylation in pancreatic beta-cells plays an important role in insulin secretion. To examine the impact of mitochondrial dysfunction on insulin secretion, we created a MIN6 cell line that depleted mitochondrial DNA (mtDNA) by treatment with ethidium bromide (EtBr), and studied the response of the cell line to various secretagogues. MIN6 cells cultured with 0.5 microg/ml EtBr for over 2 months (termed MIN6 deltamt cells) revealed a marked (>90%) decrease in mtDNA content and a lack of mRNAs encoded by mtDNA. MIN6 deltamt cells showed the defects of cytochrome c oxidase activity, glucose- and leucine-induced increase in cellular ATP content, and respiratory chain-driven ATP synthesis, suggesting that MIN6 deltamt cells lost oxidative phosphorylation activity due to the selective disruption of the subunits of respiratory chain enzymes encoded by mtDNA. MIN6 deltamt cells also showed a decrease in glucose utilization, suggesting the impairment of the glycolytic pathway as well. After stimulation with glucose and leucine, MIN6 deltamt cells showed no response in insulin secretion or intracellular free Ca2+ concentration ([Ca2+]i). On the other hand, arginine stimulated insulin secretion and an increase in [Ca2+]i in MIN6 deltamt cells as in MIN6 cells. Glibenclamide also stimulated insulin secretion and an increase in [Ca2+]i in both types of cells, but the responses of MIN6 deltamt cells were significantly lower than those of MIN6 cells. These results suggest the importance of ATP production in insulin secretion and an increase in [Ca2+]i, both induced by glucose and leucine. Moreover, mitochondrial function turns out to be not essential but important for the activation of sulfonylurea-induced insulin secretion.

Adenosine Triphosphate↗
PubMed2006

[Oxidative stress and heart failure].

The excessive reactive oxygen species (ROS), produced by the electron leak in mitochondria of failing myocardium, play an important role in development and progression of heart failure (HF) and cardiac remodeling, which is associated with induction of myocyte hypertrophy and apoptosis and activation of matrix metalloproteinases. Furthermore, ROS can damage mitochondrial DNA(mtDNA), and thus lead to mitochondrial dysfunction and additional ROS generation. Recently, we found that the overexpression of mitochondrial transcription factor A (TFAM), which is essential for mtDNA transcription and replication, ameliorates cardiac remodeling and failure. Therefore, the regulation of mitochondrial oxidative stress or manipulation of TFAM protein may provide a novel therapeutic strategy of HF.

Animals↗
PubMed1995

[Idiopathic Parkinson disease and mitochondrial functions].

Work on the molecular mechanisms of MPTP neurotoxicity have inspired search into the function of mitochondria in idiopathic Parkinson's disease. All the studies show a decrease of 30 to 40% in the activity of the respiratory complex I in the mitochondria of the nigra substantia. This decreased activity is not found in other degenerative Parkinsonisms treated with L-Dopa and cannot be explained simply by age. It is not found in other tissues including muscles and platelets. The causal mechanism of this mitochondrial dysfunction is unknown but it is not related to a mutation in mitochondrial DNA.

Humans↗
PubMed1996

Sequential acquisition of mitochondrial and plasma membrane alterations during early lymphocyte apoptosis.

When cells undergo nuclear apoptosis (chromatin condensation, DNA fragmentation), they already manifest at least three alterations that can be quantified cytofluorometrically at the single-cell level: 1) a loss of mitochondrial transmembrane potential (delta psi m), 2) an increased production of superoxide anions, and 3) the aberrant exposure of phosphatidylserine (PS) residues on the outer plasma membrane leaflet. This latter alteration allows for the phagocytic recognition/elimination of apoptotic cells. In this work, we show that cells first undergo the delta psi m disruption and that PS exposure only affects cells that already have a low delta psi m. Pharmacologic modulation of apoptosis with inhibitors of macromolecule synthesis or proteases, as well as with drugs stabilizing the delta psi m, indicates that delta psi m disruption and PS exposure are coregulated. Interventions on apoptosis-regulatory genes (p53, bcl-2) confirm the coregulation of delta-psi-m disruption, PS exposure, and nuclear signs of apoptosis. In all conditions in which apoptosis is prevented, the delta psi m remains stable and PS cannot be detected on the cell surface. Reactive oxygen species do not contribute to PS exposure, based on two lines of evidence. First, among thymocytes undergoing apoptosis in response to dexamethasone, delta psi mlow cells first expose PS and then hyperproduce superoxide anion. Second, exogenous sources of reactive oxygen species or the superoxide anion-generating drug menadione fail to cause rapid PS exposure. Instead, direct interventions on mitochondria using inhibitors of the respiratory chain or the F1 ATP synthase cause PS exposure in cells subsequent to delta psi m disruption. This effect is also obtained in anucleate cells, indicating that the nucleus does not intervene in the sequence of events coupling mitochondrial dysfunction to PS exposure. Altogether, these data underline the functional impact of mitochondrial alterations on the apoptotic process.

Animals↗
PubMed2001

Role of 4-hydroxynonenal in modification of cytochrome c oxidase in ischemia/reperfused rat heart.

Mitochondrial dysfunction is a characteristic of ischemia/reperfusion (I/R) injury in the heart. While oxidative stress has been implicated in mitochondrial damage in I/R injury, the underlying mechanisms are unclear. 4-Hydroxynonenal (HNE) is a toxic aldehyde generated by lipid peroxidation. The purpose of the present study was to assess the role of HNE in I/R-induced damage of a crucial component of the mitochondrial electron transport chain, cytochrome c oxidase (COX). I/R was induced in male WKY rats by 15 mins of ischemia followed by reperfusion for up to 3 h. COX activity was measured spectrophotometrically at 550 nm. HNE adducts with COX subunits were detected by Western Blot using an HNE-histidine antibody. HNE and reduced glutathione (GSH) contents were measured in mitochondria by HPLC. Following 3 h of reperfusion, COX activity was reduced to 59% of control, accompanied by increases in HNE adducts with COX (P<0.05). Mitochondrial HNE content in reperfused hearts was increased to 165% of control, whereas GSH was decreased to 62% of control (P<0.05). After purified COX was incubated with HNE in vitro, COX activity was decreased progressively with increasing concentrations of HNE, accompanied by concentration-dependent formation of HNE adducts with COX. GSH prevented HNE adduct formation as well as COX inhibition by HNE. These results suggest that HNE, via adduct formation with COX subunits, plays an important role in COX dysfunction caused by reperfusion. The findings also indicate that decreases in mitochondrial GSH stores in reperfused myocardium could potentiate HNE-mediated COX damage.

Aldehydes↗
PubMed1998

Mitochondrial aging: open questions.

Interest in the role of mitochondria in aging has intensified in recent years. This focus on mitochondria originated in part from the free radical theory of aging, which argues that oxidative damage plays a key role in degenerative senescence. Among the numerous mechanisms known to generate oxidants, leakage of the superoxide anion and hydrogen peroxide from the mitochondrial electron transport chain are of particular interest, due to the correlation between species-specific metabolic rate ("rate of living") and life span. Phenomenological studies of mitochondrial function long ago noted a decline in mitochondrial function with age, and on-going research continues to add to this body of knowledge. The extranuclear somatic mutation theory of aging proposes that the accumulation of mutations in the mitochondrial genome may be responsible in part for the mitochondrial phenomenology of aging. Recent studies of mitochondrial DNA (mtDNA) deletions have shown that they increase with age in humans and other mammals. Currently, there exist numerous important and fundamental questions surrounding mitochondria and aging. Among these are (1) How important are mitochondrial oxidants in determining overall cellular oxidative stress? (2) What are the mechanisms of mitochondrial oxidant generation? (3) How are lesions and mutations in mtDNA formed? (4) How important are mtDNA lesions and mutations in causing mitochondrial dysfunction? (5) How are mitochondria regulated, and how does this regulation change during aging? (6) What are the dynamics of mitochondrial turnover? (7) What is the relationship between mitochondrial damage and lipofuscinogenesis? (8) What are the relationships among mitochondria, apopotosis, and aging? and (9) How can mitochondrial function (ATP generation and the establishment of a membrane potential) and dysfunction (oxidant generation) be modulated and degenerative senescence thereby treated?

Aging↗
PubMed2005

Mitochondrial aging and dysfunction in Alzheimer's disease.

Disruptions in energy metabolism have been suggested to be a prominent feature, perhaps even a fundamental component, of Alzheimer's disease (AD). These abnormalities in cerebral metabolism precede the onset of neurological dysfunction as well as gross neuropathology of AD. These changes may stem from inhibition of mitochondrial enzymes including pyruvate dehydrogenase, cytochrome c oxidase, and alpha-ketoglutarate dehydrogenase. Several lines of evidence also suggest a role for oxidative stress in the neuropathology associated with the disease state. Because mitochondria are the major site of free radical production in cells, they are also a primary target for oxidative damage and subsequent dysfunction. This link between mitochondrial dysfunction and the pathophysiology of AD is supported by several lines of evidence.

Aging↗
PubMed1990

The molecular pathology of respiratory-chain dysfunction in human mitochondrial myopathies.

Some of the different molecular pathologies of respiratory-chain dysfunction in human mitochondrial myopathies will be reviewed in relation to the findings in 58 cases. Deletions of mitochondrial DNA were identified in 21 cases [36%]. There was some correlation between the sites of the deletion and the mitochondrial biochemistry in patients with defects of Complex I but not in cases with more extensive loss of respiratory chain activity. Complex I and Complex IV polypeptides were usually normal in deleted cases. Non-deleted cases, however, often showed specific subunit deficiencies which involved the products of both nuclear and mitochondrial genes. Immunoblots of respiratory-chain polypeptides in one case pointed to defective translocation of the Rieske precursor from the cytosol into the mitochondria. The pathogenic role of circulating autoantibodies to specific matrix proteins and the nature of the target antigens in two patients with mitochondrial encephalomyopathies and respiratory-chain dysfunction will also be discussed.

Autoantibodies↗
PubMed2006

Mitochondrial DNA mutations, energy metabolism and apoptosis in aging muscle.

Locomotor functional decline and loss in muscle mass with age is virtually a universal characteristic that has been documented in several species, including worms, fruit flies, rodents, non-human primates and humans. The age-related loss of muscle mass and strength (sarcopenia) represents an important risk factor for disability and mortality in older subjects and has been linked with cellular energy deficit and increased apoptosis at old age. Many key theories on aging describing the mechanisms underlying sarcopenia are now focused on the mitochondria because of their dichotomous role in controlling life and death processes within myocytes. Mitochondria represent the main producers of cellular energy in the form of adenosine triphosphate, but are also considered a key regulatory center of apoptosis. Unknown factors leading to a decrease in aerobic energy efficiency are linked with mitochondrial mutations which may result into apoptosis. Moreover, deregulation of autophagy (degradation and recycling of long-lived protein and organelles, such as the mitochondria) in post-mitotic tissue might also be responsible for the age-associated cellular energy failure. Alterations in specific signaling pathways, such as AMP-activated protein kinases, play a role in both cell survival response and apoptotic response depending on energy depletion. Evidence supports that apoptosis occurring in aging skeletal muscle may be due, in part, to the progressive decline in mitochondrial function and the resulting energy depletion within the cell. In turn, mitochondrial dysfunction is partly due to the accumulation of oxidative damage to macromolecules, including mitochondrial DNA, RNA and proteins, essential components for optimal functioning of mitochondria. Evidence concerning these series of events leading to energy depletion and apoptosis are discussed.

Aging↗
PubMed2026

Prioritizing Parkinson's disease risk-associated mitochondrial candidate genes via multi-omics integrative analysis.

BACKGROUND: Mitochondrial dysfunction has been implicated in Parkinson's disease (PD), but the genetically regulated mitochondrial genes associated with PD risk remain incompletely defined. METHODS: We conducted a summary-data-based genetic epidemiology study integrating summary-based Mendelian randomization (SMR), Heterogeneity in dependent instruments (HEIDI) filtering, and Bayesian colocalization to prioritize mitochondrial-related molecular features associated with PD risk. Mitochondrial-related genes were defined using MitoCarta3.0. Genetically predicted gene expression and plasma protein abundance were evaluated using expression quantitative trait loci (eQTL) data from eQTLGen and GTEx v8, and protein quantitative trait loci (pQTL) data was assessed using International Parkinson's Disease Genomics Consortium (IPDGC) as the discovery genome-wide association study (GWAS) and FinnGen as the replication dataset. Prespecified QTL analyses were interpreted using FDR correction, HEIDI filtering, and colocalization support. DNA methylation QTL analysis, mitochondrial phenotype MR, and single-nucleus RNA-seq analysis were performed as complementary analyses. RESULTS: In the primary eQTL analysis, higher genetically predicted TTC19 expression was associated with lower PD risk (OR = 0.80, 95% CI: 0.74-0.87, PPH4&#x202f;= 0.80), whereas higher MALSU1 expression was associated with increased PD risk (OR = 2.21, 95% CI: 1.59-3.06, PPH4&#x202f;= 0.96). Both associations survived FDR correction, passed HEIDI filtering, and showed colocalization support. GTEx whole-blood data supported the direction of the TTC19 association. No mitochondrial protein reached significance after FDR correction and colocalization filtering in the primary pQTL analysis. Complementary methylation analysis highlighted cg06270993 as an exploratory regulatory signal for MALSU1. CONCLUSIONS: This MR-colocalization study prioritizes TTC19 and MALSU1 as genetically supported mitochondrial-related candidate genes associated with PD risk. Further validation is required to define their functional roles in PD pathogenesis.

Humans↗
PubMed2005

Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis.

Mitochondrial dysfunction is a hallmark of cancer cells. Consistent with this phenotype mutations in mitochondrial genome have been reported in all cancers examined to date. However, it is not clear whether mitochondrial genomic status in human cells affects nuclear genome stability and whether proteins involved in inter-genomic cross talk are involved in tumorigenesis. Using cell culture model and cybrid cell technology, we provide evidence that mitochondrial genetic status impacts nuclear genome stability in human cells. In particular our studies demonstrate 1) that depletion of mitochondrial genome (rho0) leads to chromosomal instability (CIN) reported to be present in variety of human tumors and 2) rho0 cells show transformed phenotype. Our study also demonstrates that mitochondrial genetic status plays a key role in regulation of a multifunctional protein APE1 (also known as Ref1 or HAP1) involved in transcription and DNA repair in the nucleus and the mitochondria. Interestingly we found that altered expression of APE1 in rho0 cells and tumorigenic phenotype can be reversed by exogenous transfer of wild type mitochondria in rho0 cells. Furthermore, we demonstrate that APE1 expression is altered in variety of primary tumors. Taken together, these studies suggest that inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis and that APE1 mediates this process.

Blotting, Western↗
PubMed2006

Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome.

Hemizygous deletion of a 3 Mb region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (Prodh) and thioredoxin reductase 2 (Txnrd2).

Animals↗
PubMed2006

Iron dysregulation in Friedreich ataxia.

Friedreich ataxia is the most common hereditary ataxia. The signs and symptoms of the disorder derive from decreased expression of the protein frataxin, which is involved in iron metabolism. Frataxin chaperones iron for iron-sulfur cluster biogenesis and detoxifies iron in the mitochondrial matrix. Decreased expression of frataxin is associated with impairments of iron-sulfur cluster biogenesis and heme synthesis, as well as with mitochondrial dysfunction and oxidative stress. Compounds currently in clinical trials are directed toward improving mitochondrial function and lessening oxidative stress. Iron chelators and compounds that increase frataxin expression are under evaluation. Further elucidation of frataxin's function should lead to additional therapeutic approaches.

Amino Acid Sequence↗