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PubMed2000

Mitochondrial disease: beyond etiology unknown.

Mitochondrial dysfunction is now recognized as a relatively common cause of degenerative disease in children. Mutations in either the mitochondrial or the nuclear genome that cause errors in the synthesis of enzymes essential for energy production and metabolism lead to a wide variety of pediatric problems, including developmental delays, sensorimotor impairment, seizures, diabetes, and organ failure. This article reviews the role of mitochondria in health and illness, discusses the clinical aspects of mitochondrial dysfunction, describes the experiences of three children with mitochondrial disease, and presents nursing strategies for affected families.

Adult↗
PubMed2005

Aging muscle.

Age causes structural and functional changes in skeletal muscle in a wide range of species, including humans. Muscle changes in humans start in the fourth decade of life and cause frailty and disabilities. Associated changes in body composition form the basis of many metabolic disorders, such as insulin resistance, type 2 diabetes, hypertension, and hyperlipidemia, which result in an increased incidence of cardiovascular death. Decreases in the synthesis rates of many muscle proteins, specifically of myosin heavy chain and mitochondrial proteins, occur with age. The underlying causes of the reduction in mitochondrial biogenesis and ATP production seem to be decreases in mitochondrial DNA and messenger RNA. Reduced ATP production could be the basis of reduced muscle protein turnover, which requires energy. Both aerobic exercise and resistance exercise enhance muscle protein synthesis and mitochondrial biogenesis. Insulin and amino acids have also been shown to enhance muscle mitochondrial biogenesis and mitochondrial protein synthesis. However, the insulin-induced increase in muscle mitochondrial ATP production is defective in type 2 diabetic patients with insulin resistance. Moreover, a dissociation between increases in muscle mitochondrial biogenesis and insulin sensitivity after exercise has been noted in older persons. It remains to be determined whether muscle mitochondrial dysfunction causes or results from insulin resistance. Exercise seems to enhance the efficiency of muscle mitochondrial DNA in rodents. Reduced physical activity as a contributor of age-related mitochondrial dysfunction remains to be determined. It is proposed that a reduction in tissue mitochondrial ATP production signals the hypothalamic centers to reduce spontaneous physical activities. Voluntary physical activity is regulated by cognitive centers and could attenuate the progressive decline in mitochondrial functions that occurs with age.

Adult↗
PubMed1991

Hepatic polyamine metabolism in children with Reye's syndrome.

Acute mitochondrial insult has been suggested as a primary reason for the clinical, histopathological and biochemical abnormalities seen in Reye's syndrome. However, the etiology of mitochondrial dysfunction has not been identified. Polyamines have been known to alter the mitochondrial structure and function. Influenza infection may cause an increase in ornithine decarboxylase activity and thereby channel ornithine for polyamine biosynthesis, leading to mitochondrial dysfunction in Reye's syndrome. To test this hypothesis, the hepatic concentrations of polyamines, polyamine-metabolizing enzymes and urea cycle enzyme activities in Reye's syndrome patients were determined and compared with patients who died from illnesses other than Reye's syndrome. The hepatic concentration of putrescine, spermidine and spermine were increased in Reye's syndrome patients. The activity of ornithine decarboxylase was elevated but, due to the small number of samples, these values did not reach statistical significance. Ornithine carbamoyltransferase activity was decreased in the liver of Reye's syndrome patients. Our results suggest that increased synthesis of polyamines from ornithine may initiate mitochondrial injury in Reye's syndrome.

Child↗
PubMed1998

Reversibility of hepatic mitochondrial damage in rats with long-term cholestasis.

BACKGROUND/AIMS: Long-term bile duct ligation in rats is associated with secondary biliary cirrhosis and metabolic alterations, e.g. mitochondrial dysfunction. We performed the current studies to characterize the reversibility of hepatic mitochondrial dysfunction after reversing biliary obstruction by Roux-en-Y anastomosis. METHODS: Rats were studied after 4 weeks of bile duct ligation, and after 5 or 14 days of reanastomosis. Control rats were pair-fed to treated rats and all rats were studied after starvation for 24 h. Mitochondria were isolated by differential centrifugation and enzyme activities determined by spectrophotometric methods. RESULTS: In comparison to controls, plasma beta-hydroxybutyrate concentrations were decreased in bile duct ligated rats (200+/-70 vs. 790+/-200 micromol/l) and remained decreased after relief of biliary obstruction. In contrast, plasma free fatty acids were not different between controls and treated rats. Oxidative metabolism of L-glutamate, succinate and duroquinol was decreased in liver mitochondria from bile duct ligated rats. After relief of biliary obstruction, the metabolism of L-glutamate and duroquinol normalized quickly, whereas succinate metabolism remained impaired. Similar results were obtained for the mitochondrial oxidases in disrupted mitochondria. The activities of complex I, II, III and V of the respiratory chain were reduced in bile duct ligated rats. After relief of biliary obstruction, complex I and III normalized quickly, whereas complex II and V remained impaired. Oxidative metabolism of long-chain fatty acids by isolated liver mitochondria was decreased in bile duct ligated rats and did not recover after relief of biliary obstruction. CONCLUSIONS: Long-term cholestasis in the rat is associated with a decrease in specific functions of liver mitochondria which recover only partially after Roux-en-Y anastomosis. The persistence of decreased mitochondrial fatty acid metabolism cannot be explained by impaired activity of the respiratory chain, but is more likely due to alterations in mitochondrial beta-oxidation.

3-Hydroxybutyric Acid↗
PubMed2006

The key role of mitochondria in Alzheimer's disease.

Mitochondria are uniquely poised to play a pivotal role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. This review is mainly focused in the discussion of evidence suggesting a clear association between amyloid-beta toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage/death in Alzheimer's disease pathophysiology. The knowledge that mitochondrial dysfunction has a preponderant role in Alzheimer's disease opened a window for new therapeutic strategies aimed to preserve/ameliorate mitochondrial function. Based on recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of 'Mitochondrial Medicine' as a whole new field of biomedical research being this topic discussed in the last section of this review.

Alzheimer Disease↗
PubMed2003

Friedreich's Ataxia: disease mechanisms, antioxidant and Coenzyme Q10 therapy.

Mitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis. These advances in our understanding of the disease mechanisms are enabling therapeutic avenues to be explored, in particular the use of established drugs such as antioxidants and enhancers of respiratory chain function. Vitamin E therapy has been shown to be beneficial in patients with ataxia with vitamin E deficiency, and CoQ10 therapy was effective in some patients with ataxia associated with CoQ10 deficiency. A combined therapy involving long term treatment with high doses of vitamin E and coenzyme Q10 has jointly targeted two of the major features of Friedreich's Ataxia; decreased mitochondrial respiratory chain function and increased oxidative stress. This therapy clearly showed a rapid and sustained increase in the energy generated by the FRDA heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation parallel those of the heart but to a lower level. While this therapy appeared to slow the predicted progression of some clinical symptoms a larger placebo controlled study is required to confirm these observations. Other antioxidant strategies have involved the use of Idebenone, selenium and N acetyl cysteine but only the use of Idebenone has involved structured trials with relatively large patient numbers. Idebenone clearly had an impact upon the cardiac hypertrophy in the majority of patients, although there have not been any other significant benefits reported to date.

Antioxidants↗
PubMed2000

Aging enhances the activation of the permeability transition pore in mitochondria.

Aging is associated with mitochondrial dysfunction in several tissues. However, it is not known how the observed mitochondrial dysfunction is related to aging-associated tissue degeneration. We have shown previously that the activation of the permeability transition pore (PTP), which is believed to play a critical role in cell necrosis and apoptosis, is enhanced in spleen lymphocytes from old mice. Here we show that the threshold for calcium-induced, cyclosporin-sensitive, calcium release was significantly lower in isolated brain and liver mitochondria from aging mice. Thus, aging mice exhibit enhanced PTP activation in lymphocytes, brain, and liver. These results suggest that aging increases the susceptibility to calcium-dependent cell death (e.g., excitotoxicity, ischemia-reperfusion damage) in the brain, liver, and possibly other tissues. In addition, other pathways to apoptosis or necrosis that depend on PTP activation are also likely to be enhanced by aging.

Aging↗
PubMed2024

Integrated multi-omics approaches reveal the neurotoxicity of triclocarban in mouse brain.

Triclocarban (TCC) is an antimicrobial ingredient that commonly incorporated in many household and personal care products, raising public concerns about its potential health risks. Previous research has showed that TCC could cross the blood-brain barrier, but to date our understanding of its potential neurotoxicity at human-relevant concentrations remains lacking. In this study, we observed anxiety-like behaviors in mice with continuous percutaneous exposure to TCC. Subsequently, we combined lipidomic, proteomic, and metabolic landscapes to investigate the underlying mechanisms of TCC-related neurotoxicity. The results showed that TCC exposure dysregulated the proteins involved in endocytosis and neurodegenerative disorders in mouse cerebrum. Brain energy homeostasis was also altered, as evidenced by the perturbation of pyruvate metabolism, TCA cycle, and oxidative phosphorylation, which in turn caused mitochondrial dysfunction. Meanwhile, the changing trends of sphingolipid signaling pathway and overproduction of mitochondrial reactive oxygen species (mROS) could enhance the neural apoptosis. The in vitro approach further demonstrated that TCC exposure promoted apoptosis, accompanied by the overproduction of mROS and alteration in the mitochondrial membrane potential in N2A cells. Together, dysregulated endocytosis, mROS-related mitochondrial dysfunction and neural cell apoptosis are considered to be crucial factors for TCC-induced neurotoxicity, which may contribute to the occurrence and development of neurodegenerative disorders. Our findings provide novel perspectives for the mechanisms of TCC-triggered neurotoxicity.

Animals↗
PubMed2004

Region-specific analysis of mitochondrial DNA deletions in neurodegenerative disorders in humans.

Mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) aberrations has been implicated in the neuronal death in neurodegenerative disorders. Significant neuronal damage can occur if the percentage of mtDNA mutations may reach a critical threshold. mtDNA mutations also accumulate during normal aging. Here we quantified the 5 kB common mtDNA deletion (CD) using real-time PCR in various brain regions from neurodegenerative disorders and controls. We confirmed previous results that the CD levels increase with age, reaching highest levels in the basal ganglia. High CD levels were also found in affected regions in frontotemporal dementia, Parkinson's disease, and dementia with Lewy bodies, but not in Alzheimer's disease. This suggests that mtDNA damage may occur in a region-specific distribution in neurodegenerative disorders.

Adult↗
PubMed2001

Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice.

Highly active antiretroviral therapy (HAART) is implicated in cardiomyopathy (CM) and in elevated plasma lactate (LA) in AIDS through mechanisms of mitochondrial dysfunction. To determine mitochondrial events from HAART in vivo, 8-week-old hemizygous transgenic AIDS mice (NL4-3Delta gag/pol; TG) and wild-type FVB/n littermates were treated with the HAART combination of zidovudine, lamivudine, and indinavir or vehicle control for 10 days or 35 days. At termination of the experiments, mice underwent echocardiography, quantitation of abundance of molecular markers of CM (ventricular mRNA encoding atrial natriuretic factor [ANF] and sarcoplasmic calcium ATPase [SERCA2]), and determination of plasma LA. Myocardial histologic features were analyzed semiquantitatively and results were confirmed by transmission electron microscopy. After 35 days in the TG + HAART cohort, left ventricular mass increased 160% by echocardiography. Molecularly, ANF mRNA increased 250% and SERCA2 mRNA decreased 57%. Biochemically, LA was elevated (8.5 +/- 2.0 mM). Pathologically, granular cytoplasmic changes were found in cardiac myocytes, indicating enlarged, damaged mitochondria. Findings were confirmed ultrastructurally. No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG + HAART cohort. Results show that cumulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic mice.

Acquired Immunodeficiency Syndrome↗
PubMed2003

LHON and other optic nerve atrophies: the mitochondrial connection.

The clinical, biochemical and genetic features of Leber's hereditary optic neuropathy (LHON) are reviewed. The etiology of LHON is complex, but the primary risk factor is a mutation in one of the seven mitochondrial genes that encode subunits of respiratory chain complex I. The pathogenesis of LHON is not yet understood, but one plausible model is that increased or altered mitochondrial ROS production renders the retinal ganglion cells vulnerable to apoptotic cell death. In addition to LHON, there are a large number of other optic nerve degenerative disorders including autosomal dominant optic atrophy, the toxic/nutritional optic neuropathies and glaucoma. A review of the recent scientific literature suggests that these disorders also involve mitochondrial dysfunction or altered mitochondrial signaling pathways in their pathogenesis. This mitochondrial link provides new avenues of experimental investigation to these major causes of loss of vision.

DNA, Mitochondrial↗
PubMed1997

[Doxorubicin-induced myocardial damage in elderly patients with hematologic malignancies].

Cardiac function was evaluated in 53 elderly patients with hematologic malignancies who were being treated with doxorubicin (DXR). The left ventricular ejection fraction was measured by radionuclide angiocardiography, the washout rate by 123I-MIBG myocardial SPECT, the extent and severity scores by 123I-BMIPP myocardial SPECT, and the frequency of premature ventricular contractions by Holter electrocardiography. 1) In some patients, both the washout rate and the extent and severity scores were abnormally high before treatment. 2) Because the washout rate correlated with the total dose of DXR, it may be an early indicator of cardiac sympathetic nervous dysfunction. 3) The left ventricular ejection fraction correlated with the extent and severity scores, but not with the washout rate or with the frequency of premature ventricular contractions. 4) The washout rate correlated with the frequency of premature ventricular contractions. These data show that elderly patients had abnormal cardiac function even before treatment with DXR; that cardiac sympathetic dysfunction and cardiac mitochondrial dysfunction developed at total DXR doses of 250 to 300 mg/m2 or higher; and that the left ventricular ejection fraction was less than or equal to 50% in many patients. Consequently, when DXR is used to treat elderly patients, multimodal evaluation of cardiac function is necessary to detect cardiotoxicity and to determine the optimal total dose and the optimal dosage.

Aged↗
PubMed2006

Involvement of UCP3 in mild uncoupling and lipotoxicity.

Although vital to life, mitochondria are also the major source of ROS production, which may have unwanted detrimental effects on DNA, RNA and protein structures Therefore, mitochondria must exhibit well-developed mechanisms to regulate its ROS production. One such mechanism might be mild uncoupling of the mitochondrial respiratory chain, thereby lowering the proton gradient across the inner mitochondrial membrane and directly lowering ROS production. Mitochondrial uncoupling proteins have been shown to possess mild uncoupling activity and may therefore be important regulator of mitochondrial ROS production. The skeletal muscle isoform of the uncoupling protein family, UCP3, seems to be specifically active under conditions of high fatty acid availability. Although the exact function of UCP3 is not yet unravelled, UCP3 is activated by lipid peroxides and suggested to export fatty acid anions and/or peroxides from the mitochondrial matrix, thereby specifically protecting fatty acids from ROS-induced oxidative damage. Protein levels of UCP3 are reduced with aging and in the (pre)-diabetic state, both conditions characterized by increased levels of oxidative damage to lipids and proteins and reduced mitochondrial function. Whether UCP3 is causally related to mitochondrial dysfunction and is essential in the prevention and treatment of lipid-induced mitochondrial dysfunction requires further study.

Adenosine Triphosphate↗
PubMed2000

Analysis of the cytotoxic properties of linoleic acid metabolites produced by renal and hepatic P450s.

Cytochrome P450 epoxidation of linoleic acid produces biologically active metabolites which have been associated with many pathological conditions that often lead to acute renal failure. In the present study, we evaluated the ability of specific cytochrome P450s to produce linoleic acid monoepoxides. We then tested the cytotoxic properties of linoleic acid, linoleic acid monoepoxides, and corresponding diols in a rabbit renal proximal tubule model. CYP1A2, CYP2E1, CYP2J2, CYP2J3, CYP2J5, and CYP2J9 metabolized linoleic acid at rates comparable to arachidonic acid and produced linoleic acid monoepoxides as major products. Cytotoxicity studies showed that linoleic acid, linoleic acid monoepoxides, and corresponding diols are toxic at pathologically relevant concentrations (100-500 microM). Concentration-dependent studies showed that linoleic acid and linoleic acid monoepoxides are the most toxic and induce mitochondrial dysfunction prior to cell death. Cytoprotectants known to block cell death associated with mitochondrial dysfunction and oxidative stress did not prevent cell death induced by linoleic acid and linoleic acid monoepoxides. This study shows that P450s in the CYP1 and CYP2 gene families metabolize linoleic acid to linoleic acid monoepoxides and that the monoepoxides, as well as linoleic acid, disrupt mitochondrial function without causing oxidative stress.

Animals↗
PubMed2025

Methodologies for Mitochondrial Omic Profiling During Spaceflight.

To be able to understand how spaceflight can affect human biology, there is a need for maximizing the amount of information that can be obtained from experiments flown to space. Recently there has been an influx of data obtained from astronauts through multi-omics approaches based on both governmental and commercial spaceflight missions. In addition to data from humans, mitochondrial specific data is gathered for other experiments from rodents and other organisms that are flown in space. This data has started to universally demonstrate that mitochondrial dysfunction is the key regulator associated with increasing health risks associated with spaceflight. This mitochondrial dysfunction can have influence downstream on immune suppression, inflammation, circadian rhythm issues, and more. Due to the space environment, standard methodologies have to be altered for performing mitochondrial specific analysis and in general sample collection for omics. To perform mitochondrial specific analysis and data collection from samples flown to space we will outline the current sample collection methods, processing of the samples, and specific analysis. Specifically we will highlight the different mitochondrial methodologies and challenges involved with research associated with spaceflight.

Space Flight↗
PubMed2004

Carvedilol protects ischemic cardiac mitochondria by preventing oxidative stress.

Ischemia negatively affects mitochondrial function by inducing the mitochondrial permeability transition (MPT). The MPT is triggered by oxidative stress, which occurs in mitochondria during ischemia as a result of diminished antioxidant defenses and increased reactive oxygen species production. It causes mitochondrial dysfunction and can ultimately lead to cell death. Therefore, drugs able to minimize mitochondrial damage induced by ischemia may prove to be clinically effective. We analyzed the effect of carvedilol, a beta-blocker with antioxidant properties, on mitochondrial dysfunction. Carvedilol decreased levels of TBARS (thiobarbituric acid reactive substances), an indicator of oxidative stress, which is consistent with its antioxidant properties. Regarding cell death by apoptosis, although ischemia did increase caspase-8-like activity, there were no changes in caspase-3-like activity, which is activated downstream of caspase-8; this may indicate that the apoptotic cascade is not activated by 60 minutes of ischemia. We conclude that carvedilol protects ischemic mitochondria by preventing oxidative mitochondrial damage, and, by so doing, it may also inhibit the formation of the MPT pore.

Adrenergic beta-Antagonists↗
PubMed2006

Transcriptional profiling for understanding the basis of mitochondrial involvement in disease and toxicity using the mitochondria-specific MitoChip.

It is well documented that mitochondrial dysfunction significantly contributes to a number of degenerative diseases, metabolic disorders, and drug- and chemical-induced toxicities. Thus far, information gained by several molecular and biochemical techniques used to delineate the mechanism of impaired mitochondrial activity underlying different diseases and various toxicities is still limited due to their low throughput potential. Here, we describe the development of mitochondria-specific mouse oligonucleotide microarray and its potential to define mechanisms of disease progression and drug toxicities associated with mitochondrial dysfunction at both nuclear and mitochondrial genome level.

Animals↗
PubMed2025

Peri-mitochondrial actin filaments inhibit Parkin assembly by disrupting ER-mitochondria contacts.

Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.

Ubiquitin-Protein Ligases↗