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PubMed2003

In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington's disease.

The mechanisms by which neurons die in CAG triplet repeat (polyglutamine) disorders, such as Huntington's disease, are uncertain; however, mitochondrial dysfunction and disordered calcium homeostasis have been implicated. We previously demonstrated abnormal mitochondrial calcium handling in Huntington's disease cell lines and transgenic mice. To examine whether these abnormalities might arise in part from direct effects of the expanded polyglutamine tract contained in mutant huntingtin, we have exposed normal rat liver and human lymphoblast mitochondria to glutathione S-transferase fusion proteins containing polyglutamine tracts of 0, 19, or 62 residues. Similar to bovine serum albumin, each of the protein constructs nonspecifically inhibited succinate-supported respiration, independent of polyglutamine tract length. There was a small but significant reduction of mitochondrial membrane potential (state 4) only in the presence of the pathological-length polyglutamine tract. With successive addition of small Ca(2+) aliquots, mitochondria exposed to pathological-length polyglutamine tracts (approximately 5 microM) depolarized much earlier and to a greater extent than those exposed to the other protein constructs. These results suggest that the mitochondrial calcium handling defects seen in Huntington's disease cell lines and transgenic mice may be due, in part, to direct, deleterious effects of mutant huntingtin on mitochondria.

Animals↗

PubMed1999

Ruptured abdominal aortic aneurysm, a "two-hit" ischemia/reperfusion injury: evidence from an analysis of oxidative products.

PURPOSE: Ruptured abdominal aortic aneurysm (RAAA) remains a lethal condition despite improvements in perioperative care. The consequences of RAAA are hypothesized to result from a combination of two ischemia/reperfusion events: hemorrhagic shock and lower torso ischemia. Ischemia/reperfusion results in tissue injury by diverse mechanisms, which include oxygen free radical-mediated injury produced from activated neutrophils, xanthine oxidase, and mitochondria. Oxygen-free radicals attack membrane lipids, resulting in membrane and subsequently cellular dysfunction that contributes to postoperative organ injury/failure. The purpose of this investigation was to quantify the oxidative injury that occurs as a result of the ischemia/reperfusion events in RAAAs and elective AAAs. METHODS: Blood samples were taken from 22 patients for elective AAA repair and from 14 patients for RAAA repair during the perioperative period. Plasma F(2)-isoprostanes were extracted, purified, and measured with an enzyme immunoassay. Aldehydes and acyloins were purified and quantified. Neutrophil oxidative burst was measured in response to a receptor independent stimulus (phorbol 12-myristate 13-acetate) with luminol-based chemiluminescence. RESULTS: Plasma from patients with RAAAs showed significantly elevated F(2)-isoprostane levels on arrival at hospital and were significantly elevated as compared with the levels of patients for elective repair throughout the perioperative period (two-way analysis of variance, P <.0001). Multiple regression showed a significant relationship between the phagocyte oxidative activity and F(2)-isoprostane levels (P <.013). Total acyloin levels were significantly higher in patients with RAAAs as compared with the levels in elective cases. CONCLUSION: The F(2)-isoprostane levels, specific markers of lipid peroxidation, showed that patients with RAAAs had two phases of oxidative injury: before arrival at hospital and after surgery. The significant relationship between the postoperative increases in F(2)-isoprostane levels and the neutrophil oxidant production implicates neutrophils in the oxidative injury that occurs after RAAA. New therapeutic interventions that attenuate neutrophil-mediated oxidant injury during reperfusion may decrease organ failure and ultimately mortality in patients with RAAAs.

Aldehydes↗

PubMed2006

Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons.

Mitochondrial dysfunction is an underpinning event in many neurodegenerative disorders. Less clear, however, is how mitochondria become injured during neuronal demise. Nitric oxide (NO) evokes rapid mitochondrial fission in cortical neurons. Interestingly, proapoptotic Bax relocates from the cytoplasm into large foci on mitochondrial scission sites in response to nitrosative stress. Antiapoptotic Bcl-xL does not prevent mitochondrial fission despite its ability to block Bax puncta formation on mitochondria and to mitigate neuronal cell death. Mitofusin 1 (Mfn1) or dominant-negative dynamin-related protein 1(K38A) (Drp1(k38A)) inhibits mitochondrial fission and Bax accumulation on mitochondria induced by exposure to an NO donor. Although NO is known to cause a bioenergetic crisis, lowering ATP by glycolytic or mitochondrial inhibitors neither induces mitochondrial fission nor Bax foci formation on mitochondria. Taken together, these data indicate that the mitochondrial fission machinery acts upstream of the Bcl-2 family of proteins in neurons challenged with nitrosative stress.

Adenosine Triphosphate↗

PubMed2006

Contribution of somatic mutations in the mitochondrial genome to the development of cancer and tolerance against anticancer drugs.

Mitochondrial defects have long been suspected to play an important role in the development of cancer. Although most cancer cells harbor somatic mutations in mitochondrial DNA (mtDNA), the question of whether such mutations positively contribute to the development of cancer remained unclear. To clarify the role of mutant mtDNA excluding effects by the nuclear background, we focus on a method of transmitochondrial cybrids. Tumors were formed by transplanting cybrids with or without mutant mtDNA into nude mice and compared each size, revealing that mutant cybrids enhanced tumorigenesis. Next, we discuss a method for excluding the possibility of secondary nuclear mutations that may affect tumorigenesis. Mitochondrial genes that had been converted from mitochondrial to nuclear codons and equipped with a mitochondrial-targeting sequence were introduced into the nucleus of mutant cybrids. The gene products complemented the dysfunction, and reduced the promotion of tumors. By these methods, we concluded that mutant mitochondria positively and directly contribute to tumorigenesis. Since apoptosis occurred less frequently in the mutant versus wild-type cybrids in tumors, pathogenic mtDNA mutations contribute to the promotion of tumors by preventing apoptosis. Finally, we discuss the role of mutant mtDNA in conferring tolerance against anticancer drugs.

Animals↗

PubMed1998

Mt-Hsp70 homolog, Ssc2p, required for maturation of yeast frataxin and mitochondrial iron homeostasis.

Here we show that the yeast mitochondrial chaperone Ssc2p, a homolog of mt-Hsp70, plays a critical role in mitochondrial iron homeostasis. Yeast with ssc2-1 mutations were identified by a screen for altered iron-dependent gene regulation and mitochondrial dysfunction. These mutants exhibit increased cellular iron uptake, and the iron accumulates exclusively within mitochondria. Yfh1p is homologous to frataxin, the human protein implicated in the neurodegenerative disease, Friedreich's ataxia. Like mutants of yfh1, ssc2-1 mutants accumulate vast quantities of iron in mitochondria. Furthermore, using import studies with isolated mitochondria, we demonstrate a specific role for Ssc2p in the maturation of Yfh1p within this organelle. This function for a mitochondrial Hsp70 chaperone is likely to be conserved, implying that a human homolog of Ssc2p may be involved in iron homeostasis and in neurodegenerative disease.

Fungal Proteins↗

PubMed2002

Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase.

A high throughput screen for neutral, magnesium-dependent sphingomyelinase (SMase) was performed. One inhibitor discovered in the screen, GW4869, functioned as a noncompetitive inhibitor of the enzyme in vitro with an IC(50) of 1 microm. It did not inhibit acid SMase at up to at least 150 microm. The compound was then evaluated for its ability to inhibit tumor necrosis factor (TNF)-induced activation of neutral SMase (N-SMase) in MCF7 cells. GW4869 (10 microm) partially inhibited TNF-induced sphingomyelin (SM) hydrolysis, and 20 microm of the compound was protected completely from the loss of SM. The addition of 10-20 microm GW4869 completely inhibited the initial accumulation of ceramide, whereas this effect was partially lost at later time points (24 h). These data therefore support the inhibitory action of GW4869 on N-SMase not only in vitro but also in a cellular model. The addition of GW4869 at both 10 and 20 microm did not modify cellular glutathione levels in response to TNF, suggesting that the action of GW4869 occurred downstream of the drop in glutathione, which was shown previously to occur upstream of the activation of N-SMase. Further, whereas TNF treatment also caused a 75% increase of de novo synthesized ceramide after 20 h of incubation, GW4869, at either 10 or 20 microm, had no effect on this pathway of ceramide generation. In addition, GW4869 did not significantly impair TNF-induced NF-kappaB translocation to nuclei. Therefore, GW4869 does not interfere with other key TNF-mediated signaling effects. GW4869 was able, in a dose-dependent manner, to significantly protect from cell death as measured by nuclear condensation, caspase activation, PARP degradation, and trypan blue uptake. These protective effects were accompanied by significant inhibition of cytochrome c release from mitochondria and caspase 9 activation, therefore localizing N-SMase activation upstream of mitochondrial dysfunction. In conclusion, our results indicate that N-SMase activation is a necessary step for the full development of the cytotoxic program induced by TNF.

Aniline Compounds↗

PubMed1997

Xq28-linked noncompaction of the left ventricular myocardium: prenatal diagnosis and pathologic analysis of affected individuals.

Isolated noncompaction of the left ventricular myocardium (INVM) is characterized by the presence of numerous prominent trabeculations and deep intertrabecular recesses within the left ventricle, sometimes also affecting the right ventricle and interventricular septum. Familial occurrence of this disorder was described previously. We present a family in which 6 affected individuals demonstrated X-linked recessive inheritance of this trait. Affected relatives presented postnatally with left ventricular failure and arrhythmias, associated with the pathognomonic echocardiographic findings of INVM. The usual findings of Barth syndrome (neutropenia, growth retardation, elevated urinary organic acids, low carnitine levels, and mitochondrial abnormalities) were either absent or found inconsistently. Fetal echocardiograms obtained between 24-30 weeks of gestation in 3 of the affected males showed a dilated left ventricle in one heart, but were not otherwise diagnostic of INVM in any of the cases. Four of the affected individuals died during infancy, one is in cardiac failure at age 8 months, and one is alive following cardiac transplant at age 9 months. The hearts from infants who died or underwent transplantation appeared, on gross examination, to be enlarged, with coarse, deep ventricular trabeculations and prominent endocardial fibroelastosis. Histologically, there were loosely organized fascicles of myocytes in subepicardial and midmyocardial zones of both ventricles, and the myocytes showed thin, often angulated fibers with prominent central clearing and reduced numbers of filaments. Markedly elongated mitochondria were present in some ventricular myocytes from one specimen, but this finding was not reproducible. Genetic linkage analysis has localized INVM to the Xq28 region, where other myopathies with cardiac involvement have been located.

Adolescent↗

PubMed2003

On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria.

Recent studies in desmin (-/-) mice have shown that the targeted ablation of desmin leads to pathological changes of the extrasarcomeric intermediate filament cytoskeleton, as well as structural and functional abnormalities of mitochondria in striated muscle. Here, we report on a novel heterozygous single adenine insertion mutation (c.5141_5143insA) in a 40-year-old patient with a distal myopathy. The insertion mutation leads to a frameshift and a truncated desmin (K239fs242). Using transfection studies in SW13 and BHK21 cells, we show that the K239fsX242 desmin mutant is incapable of forming a desmin intermediate filament network. Furthermore, it induces the collapse of a pre-existing desmin cytoskeleton, alters the subcellular distribution of mitochondria and leads to abnormal cytoplasmic protein aggregates reminiscent of desmin-immunoreactive granulofilamentous material seen in the ultrastructural analysis of the patient's muscle. Analysis of mitochondrial function in isolated saponin-permeablized skeletal muscle fibres from our patient showed decreased maximal rates of respiration with the NAD-dependent substrate combination glutamate and malate, as well as a higher amytal sensitivity of respiration, indicating an in vivo inhibition of complex I activity. Our findings suggest that the heterozygous K239fsX242 desmin insertion mutation has a dominant negative effect on the polymerization process of desmin intermediate filaments and affects not only the subcellular distribution, but also biochemical properties of mitochondria in diseased human skeletal muscle. As a consequence, the intermediate filament pathology-induced mitochondrial dysfunction may contribute to the degeneration/regeneration process leading to progressive muscle dysfunction in human desminopathies.

Adenine↗

PubMed1984

The role of phospholipase in mitochondrial dysfunction after coronary reperfusion in the canine myocardium.

The left anterior descending coronary artery of a dog was occluded for 15 min followed by a 5 min reperfusion in order to investigate the mechanism responsible for the paradoxical exacerbation of heart mitochondrial dysfunction caused by reperfusion. The mitochondrial function was assessed and the concentration of Ca++, phospholipids and free fatty acids (FFA) were determined. The relative importance of mitochondrial lysophospholipids was also investigated. Eleven dogs (30.6%) developed "reperfusion arrhythmia" (arrhythmia group) but 25 did not (control group). Although mitochondrial dysfunction was observed in the reperfused area even in the control group, a greater impairment of mitochondrial function was observed in the reperfused area in the arrhythmia group. There was no significant difference in the contents of FFA and phospholipids in the mitochondria from the normal area of both groups and from the reperfused area of the control group. However, a marked increase in eight FFA and a significant decrease in phospholipids were observed in the mitochondria from the reperfused area of the arrhythmia group. A significant increase in Ca++ content both in the myocardium and the mitochondria from the reperfused area was observed in the arrhythmia group but not in the control group. In separate experiments, the mitochondria prepared from dog left ventricle were incubated with either phospholipase C (PhC) or phospholipase A2 ( PhA2 ). Both phospholipases induced severe mitochondrial dysfunction. PhC induced a significant increase in FFA, quite analogous to the changes in mitochondrial FFA caused by reperfusion in vivo. PhA2 also induced a tremendous increase in FFA but only in the content of unsaturated FFA. Although PhC did not affect the lysophospholipid profiles, PhA2 induced lysophosphatidyl choline. These results indicate that mitochondrial damages characteristic of the early phase of coronary reperfusion may be caused by the action of PhC, activated by increased intracellular Ca++, which in turn induces degradation of the mitochondrial membrane.

Acyl Coenzyme A↗

PubMed2006

Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury.

Mitochondrial dysfunction and internucleosomal DNA fragmentation are well-recognized features of acetaminophen (AAP)-induced hepatocyte cell death. However, the endonucleases responsible for this effect have not been identified. Apoptosis-inducing factor (AIF) and endonuclease G are nucleases located in the intermembrane space of mitochondria. AIF is thought to trigger chromatin condensation and induce cleavage of DNA into high molecular weight fragments (50-300 kb), and endonuclease G can produce oligonucleosomal DNA fragments. Therefore, the objective of this investigation was to test the hypothesis that endonuclease G and AIF could be involved in AAP-induced nuclear DNA fragmentation. Using immunofluorescence microscopy, it was shown that in primary cultured mouse hepatocytes, endonuclease G and AIF translocated to the nucleus between 3 and 6 h after exposure to 5 mM AAP. In contrast, other mitochondrial intermembrane proteins such as cytochrome c or the second mitochondria-derived activator of caspases (Smac) did not accumulate in the nucleus. The translocation of AIF and endonuclease G correlated with mitochondrial dysfunction as indicated by the progressive loss of the mitochondrial membrane potential (measured with the JC-1 assay) and the appearance of nuclear DNA fragments in the cytosol (determined by an anti-histone ELISA). Pretreatment with 20mM N-acetylcysteine prevented mitochondrial dysfunction, the nuclear translocation of endonuclease G and AIF, and the nuclear DNA fragmentation. The data support the conclusion that endonuclease G and AIF translocate to the nucleus in response to AAP-induced mitochondrial dysfunction and may be responsible, at least in part, for the initial DNA fragmentation during AAP hepatotoxicity.

Acetaminophen↗

PubMed2004

Gene expression analysis in mitochondria from chagasic mice: alterations in specific metabolic pathways.

Cardiac hypertrophy and remodelling in chagasic disease might be associated with mitochondrial dysfunction. In the present study, we characterized the cardiac metabolic responses to Trypanosoma cruzi infection and progressive disease severity using a custom-designed mitoarray (mitochondrial function-related gene array). Mitoarrays consisting of known, well-characterized mitochondrial function-related cDNAs were hybridized with 32P-labelled cDNA probes generated from the myocardium of mice during immediate early, acute and chronic phases of infection and disease development. The mitoarray successfully identified novel aspects of the T. cruzi-induced alterations in the expression of the genes related to mitochondrial function and biogenesis that were further confirmed by real-time reverse transcriptase-PCRs. Of note is the up-regulation of transcripts essential for fatty acid metabolism associated with repression of the mRNAs for pyruvate dehydrogenase complex in infected hearts. We observed no statistically significant changes in mRNAs for the enzymes of tricarboxylic acid cycle. These results suggest that fatty acid metabolism compensates the pyruvate dehydrogenase complex deficiencies for the supply of acetyl-CoA for a tricarboxylic acid cycle, and chagasic hearts may not be limited in reduced energy (NADH and FADH2). The observation of a decrease in mRNA level for several subunits of the respiratory chain complexes by mitoarray as well as global genome analysis suggests a limitation in mitochondrial oxidative phosphorylation-mediated ATP-generation capacity as the probable basis for cardiac homoeostasis in chagasic disease.

Animals↗

PubMed2003

Calcium influx through receptor-operated channel induces mitochondria-triggered paraptotic cell death.

We address the specific role of cytoplasmic Ca(2+) overload as a cell death trigger by expressing a receptor-operated specific Ca(2+) channel, vanilloid receptor subtype 1 (VR1), in Jurkat cells. Ca(2+) uptake through the VR1 channel, but not capacitative Ca(2+) influx stimulated by the muscarinic type 1 receptor, induced sustained intracellular [Ca(2+)] rises, exposure of phosphatidylserine, and cell death. Ca(2+) influx was necessary and sufficient to induce mitochondrial damage, as assessed by opening of the permeability transition pore and collapse of the mitochondrial membrane potential. Ca(2+)-induced cell death was inhibited by ruthenium red, protonophore carbonyl cyanide m-chlorophenylhydrazone, or cyclosporin A treatment, as well as by Bcl-2 expression, indicating that this process requires mitochondrial calcium uptake and permeability transition pore opening. Cell death occurred without caspase activation, oligonucleosomal/50-kilobase pair DNA cleavage, or release of cytochrome c or apoptosis inducer factor from mitochondria, but it required oxidative/nitrative stress. Thus, Ca(2+) influx triggers a distinct program of mitochondrial dysfunction leading to paraptotic cell death, which does not fulfill the criteria for either apoptosis or necrosis.

Animals↗

PubMed2005

Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS.

Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2', 3'-didehydro-2', 3'-deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3' azido-3'-deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo.

BACKGROUND AND PURPOSE: The mitochondrial permeability transition pore (mPTP), an energy-dissipating channel activated by calcium, contributes to reperfusion damage by depolarizing the mitochondrial inner membrane potential. As mitochondrial Ca(2+) overload is a main inductor of mPTP opening, we examined the effect of Ru(360), a selective inhibitor of the mitochondrial calcium uptake system against myocardial damage induced by reperfusion in a rat model. EXPERIMENTAL APPROACH: Myocardial reperfusion injury was induced by a 5-min occlusion of the left anterior descending coronary artery, followed by a 5-min reperfusion in anaesthetized open-chest rats. We measured reperfusion-induced arrhythmias and functions indicative of unimpaired mitochondrial integrity to evaluate the effect of Ru(360) treatment. KEY RESULTS: Reperfusion elicited a high incidence of arrhythmias, haemodynamic dysfunction and loss of mitochondrial integrity. A bolus intravenous injection of Ru(360) (15-50 nmol kg(-1)), given 30-min before ischaemia, significantly improved the above mentioned variables in the ischaemic/reperfused myocardium. Calcium uptake in isolated mitochondria from Ru(360)-treated ventricles was partially diminished, suggesting an interaction of this compound with the calcium uniporter. CONCLUSIONS AND IMPLICATIONS: We showed that Ru(360) treatment abolishes the incidence of arrhythmias and haemodynamic dysfunction elicited by reperfusion in a whole rat model. Ru(360) administration partially inhibits calcium uptake, preventing mitochondria from depolarization by the opening of the mPTP. We conclude that myocardial damage could be a consequence of failure of the mitochondrial network to maintain the membrane potential at reperfusion. Hence, it is plausible that Ru(360) could be used in reperfusion therapy to prevent the occurrence of arrhythmia.

Aconitate Hydratase↗

PubMed2003

Cardiac and renal mitochondria respond differently to hydrogen peroxide in suckling rats.

BACKGROUND: Overwhelming septicemia with multiple organ failure is one of the main causes of mortality with neonatal surgery. Liver, kidney, and heart are organs for which oxidative metabolism is particularly important. Hydrogen peroxide (H(2)O(2)), a major mediator of sepsis, inhibits liver metabolism. Our aim was to determine the effects of H(2)O(2) on neonatal renal and cardiac oxidative metabolism. MATERIALS AND METHODS: Mitochondria were isolated from the heart and kidney of 11 to 15-day-old rats. Oxygen consumption was measured polarographically in mitochondria incubated with different concentrations of H(2)O(2). State 3 oxygen consumption, which represents maximum mitochondrial oxidative flux, was measured in the presence of adenosine diphosphate. State 4 oxygen consumption, which represents oxygen consumption that is wasted and not used for adenosine triphosphate (ATP) generation, was measured after all adenosine diphosphate was used. beta-Oxidation flux and carnitine palmitoyltransferase I activity were measured radiochemically with increased levels of H(2)O(2). RESULTS: H(2)O(2) impaired state 3 oxygen consumption at all concentrations tested in cardiac and renal mitochondria. H(2)O(2) had no significant effect on heart mitochondrial state 4 oxygen consumption but significantly increased that of kidney. Heart, but not kidney, beta-oxidation flux was inhibited by H(2)O(2). Neither cardiac nor renal carnitine palmitoyltransferase I activity was affected by H(2)O(2). CONCLUSIONS: H(2)O(2) inhibits maximal rates of ATP generation by heart and kidney mitochondria but has a more severe effect on kidney mitochondria because more oxygen is wasted and not used for ATP generation. This decrease in ATP generation may be a factor in the dysfunction of these organs during sepsis.

Adenosine Triphosphate↗

PubMed2002

Mitochondrial abnormalities in muscle and other aging cells: classification, causes, and effects.

The involvement of mitochondria and of mitochondrial DNA (mtDNA) in the aging process has generated much interest and even more controversy. The mitochondrial theory of aging considers a vicious circle consisting of: (1) accumulation of somatic mtDNA mutations; (2) impairment of respiratory chain function; (3) increased production of reactive oxygen species (ROS) in mitochondria; and (4) further damage to mtDNA. We review the evidence for and against the belief that these steps occur in aging muscle and brain, considering separately morphological, biochemical, and molecular data. The relationship between mitochondrial aging and late-onset neurodegenerative diseases is briefly reviewed. We conclude that mitochondrial dysfunction does play a crucial role in the aging process of both muscle and brain, but it remains unclear whether mitochondria are the culprits or mere accomplices.

Animals↗

PubMed2005

Effect of female age on mouse oocyte developmental competence following mitochondrial injury.

Oocytes from aging ovaries contain mitochondria with morphological and genetic flaws. How these flaws relate to phenotypes of oocyte developmental compromise associated with clinical infertility is not well understood. This study was conducted to investigate the role of mitochondria in the developmental compromises observed with female aging using a mouse model of mitochondrial dysfunction. Oocytes obtained from aging (30-40 wk) (C57BL/6J x CBACaH)F1 (B6CBAF1) hybrid female mice were photosensitized with mitochondrial fluorophore rhodamine-123 for variable durations and compared to similarly treated oocytes derived from pubertal mice (4-6 wk). Blastocyst development of normally fertilized oocytes from both age-groups correlated negatively in mathematically unique profiles with irradiation time, with a more sudden decline in development for oocytes from aging mice. Complete inhibition of blastocyst development occurred following a shorter duration of photosensitization for oocytes from aging compared to pubertal animals (60 vs. 90 sec). Prolonged photosensitization resulted in mitochondrial uncoupling and promoted localized generation of reactive oxygen species, mitochondrial permeabilization, and apoptotic phenotypes. Thus, aging oocytes are more developmentally sensitive to mitochondrial damage than pubertal oocytes but undergo similar metabolic and apoptotic responses. These and future findings may encourage further optimization of laboratory-based strategies to minimize mitochondrial injury to oocytes, particularly those from older women, and improve clinical outcomes for women with age-related etiologies of infertility.

Age Factors↗

PubMed1982

Mechanism of mitochondrial damage after coronary reperfusion.

We investigated the mechanism of the reperfusion-accelerated mitochondrial dysfunction. To clarify this mechanism, we performed the following experiments using 40 mongrel dogs. Experiment I: Prostaglandin (PG) E and F2 alpha levels in the great cardiac vein (GCV) were examined before, during occlusion and after reperfusion of the left anterior descending coronary artery (LAD). Experiment II: Heart mitochondria were prepared from the normal area and the occluded or the reperfused area after 15 min of the LAD occlusion, or after 5 min of reperfusion following the occlusion with or without premedication of indomethacin. The PGE level in the GCV did not change significantly during occlusion, but increased significantly soon after reperfusion. Mitochondrial dysfunction was caused by occlusion and further accelerated by reperfusion. The PG E level in mitochondria isolated from the reperfused area increased significantly. Indomethacin significantly prevented both the increase in PG E and the acceleration of mitochondrial dysfunction by reperfusion. These results suggest that the increase in PG E level is closely related to the reperfusion-accelerated mitochondrial dysfunction, and that premedication with indomethacin significantly prevented the extension of mitochondrial dysfunction induced by coronary reperfusion.

Animals↗