Formation of gigantic mitochondria in hypoxic isolated perfused rat hearts

Sun, Chao; Dhalla, Naranjan S.; Olson, Robert E.

doi:10.1007/bf01897616

Cited by 42 publications

(20 citation statements)

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“…The synchronous depolarization and repolarization of mitochondrial membrane potential in response to low levels of oxidative stress occurred throughout the whole length of the elongated mitochondrion, providing strong confirmation that we were visualizing a single functional unit. Interestingly, previous electron microscopy studies have observed individual mitochondria Ͼ2 to 3 sarcomeres in length, 26,27 and as far back as 1969, Sun and coworkers 28 demonstrated elongated mitochondria ranging from 3 to 7 sarcomeres in length in isolated perfused adult rat hearts in response to short periods of hypoxia (3 to 7 minutes). This raises the interesting, although at this point speculative, possibility that short nonlethal periods of hypoxia may have induced mitochondrial elongation as an endogenous protective mechanism against further hypoxic or ischemic insult.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury

et al. 2010

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Background-Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/ reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury. Methods and Results-In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Transfection of HL-1 cells with the mitochondrial fusion proteins mitofusin 1 or 2 or with Drp1 K38A , a dominantnegative mutant form of Drp1, increased the percentage of cells containing elongated mitochondria (65Ϯ4%, 69Ϯ5%, and 63Ϯ6%, respectively, versus 46Ϯ6% in control: nϭ80 cells per group; PϽ0.05), decreased mitochondrial permeability transition pore sensitivity (by 2.4Ϯ0.5-, 2.3Ϯ0.7-, and 2.4Ϯ0.3-fold, respectively; nϭ80 cells per group; PϽ0.05), and reduced cell death after simulated ischemia/reperfusion injury (11.6Ϯ3.9%, 16.2Ϯ3.9%, and 12.1Ϯ2.9%, respectively, versus 41.8Ϯ4.1% in control: nϭ320 cells per group; PϽ0.05). Treatment of HL-1 cells with mitochondrial division inhibitor-1, a pharmacological inhibitor of Drp1, replicated these beneficial effects. Interestingly, elongated interfibrillar mitochondria were identified in the adult rodent heart with confocal and electron microscopy, and in vivo treatment with mitochondrial division inhibitor-1 increased the percentage of elongated mitochondria from 3.6Ϯ0.5% to 14.5Ϯ2.8% (Pϭ0.023). Finally, treatment of adult murine cardiomyocytes with mitochondrial division inhibitor-1 reduced cell death and inhibited mitochondrial permeability transition pore opening after simulated ischemia/reperfusion injury, and in vivo treatment with mitochondrial division inhibitor-1 reduced myocardial infarct size in mice subject to coronary artery occlusion and reperfusion (21.0Ϯ2.2% with mitochondrial division inhibitor-1 versus 48.0Ϯ4.5% in control; nϭ6 animals per group; PϽ0.05). Conclusion-Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, suggesting a novel pharmacological strategy for cardioprotection. Key Words: cardiomyocytes Ⅲ hypoxia Ⅲ ischemia Ⅲ myocardial infarction Ⅲ reperfusion I nnovative treatment strategies for protecting the heart from ischemia/reperfusion injury (IRI) are needed to improve clinical outcomes in patients with coronary heart disease. Previous studies suggest that mitochondria are highly dynamic and that changes in mitochondrial shape can affect a variety of biological processes such as apoptosis, respiration, mitosis, and development. 1,2 Mitochondria change their morphology by undergoing either fusion or fission, resulting in either elongated, tubular, interconnected mitochondrial networks or fragmented, discontinuous mitochondria, respectively. 1,2 These 2 opposing processes are regulated by the mitochondrial fusion proteins mitofusin (Mfn) 1, Mfn2, and optic atrophy protein 1 and the mitochondrial fission proteins dynamin-related...

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Section: Discussionmentioning

confidence: 99%

Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury

et al. 2010

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“…As a result, relative hypoxia in the cell may be induced. Hypoxia and anoxia are known to induce MG in heart and skeletal muscles (169)(170)(171)(172)(173)(174)(175)(176). Thus, relative hypoxia possibly induced by hydrazine may cause the formation of MG.…”

Section: Free Radicals and Mg Formationmentioning

confidence: 99%

Megamitochondria formation ‐ physiology and pathology

Wakabayashi

2002

J Cellular Molecular Medi

163

120

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Mitochondria undergo structural changes simultaneously with their functional changes in both physiological and pathological conditions. These structural changes of mitochondria are classified into two categories: simple swelling and the formation of megamitochondria (MG). Data have been accumulated to indicate that free radicals play a crucial role in the mechanism of the MG formation induced by various experimental conditions which are apparently various. These include ethanol-, chloramphenicol-and hydrazine-induced MG formation. Involvement of free radicals in the mechanism of MG formation is showed by the fact that MG formation is successfully suppressed by free radical scavengers such as α-tocopherol, coenzyme Q 10 , and 4-OH-TEMPO. Detailed mechanisms and pathophysiological meanings of MG formation still remain to be investigated. However, a body of evidence strongly suggests that enormous changes in physicochemical and biochemical properties of the mitochondrial membranes during MG formation take place and these changes are favorable for membrane fusion. A recent report showed that continous exposure of cells with MG to free radicals induces apoptosis, finding which suggests that MG formation is an adaptative process to unfavorable environments at the level of intracellular organelles. Mitochondria try to decrease intracellular reactive oxygen species (ROS) levels by decreasing the consume of oxygen via MG formation. If mitochondria succeed to suppress intracellular ROS levels, MG return to normal both structurally and functionally, and they restore the ability to actively synthesize ATP. If cells are additionally exposed to excess amounts of free radicals, MG become swollen, membrane potential of mitochondria (∆Ψm) decreases, cytochrome c is released from mitochondria, leading to activation of caspases and apoptosis is induced.

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“…It is evident, therefore, that caution should be exercised in interpreting changes in mitochondrial volume as necessarily indicating the development of myocardial hypertrophy, even though other evidence [28,52,60,61] indicates that these changes do occur in early stages of hyper (156) trophy. The occurrence of mitochondrial fusion during mild hypox ia and hypertrophy has been documented by other studies [37,74,86] but its significance is unclear. On the basis of our experience with myo cardial biopsies in patients with cardiomyopathies, we consider that the finding of marked irregularity in mitochondrial size provides a better in dication of the development of cardiac hypertrophy and true reproduc tion of mitochondria.…”

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confidence: 89%