Aging and diabetes: Mitochondrial dysfunction

Irving, Brian A.; Nair, K. Sreekumaran

doi:10.1007/s11892-007-0039-x

Cited by 12 publications

(4 citation statements)

References 30 publications

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“…Several studies have documented the role of mitochondrial dysfunction in the pathophysiology of T2DM [66, 88, 124-128]. Reduced mitochondrial respiration, ATP production and mitochondrial density and mRNA have been reported in the insulin resistance and type 2 diabetic patients [54, 96, 129-132].…”

Section: Mechanistic Link Between Diabetes and Oxidative Stress/mimentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in metabolic disorders — A step towards mitochondria based therapeutic strategies

Bhatti

Reddy

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

1,086

644

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Mitochondria are the powerhouses of the cell and are involved in essential functions of the cell, including ATP production, intracellular Ca2+ regulation, reactive oxygen species production & scavenging, regulation of apoptotic cell death and activation of the caspase family of proteases. Mitochondrial dysfunction and oxidative stress are largely involved in aging, cancer, age-related neurodegenerative and metabolic syndrome. In the last decade, tremendous progress has been made in understanding mitochondrial structure, function and their physiology in metabolic syndromes such as diabetes, obesity, stroke and hypertension, heart disease. Further, progress has also been made in developing therapeutic strategies, including lifestyle interventions (healthy diet and regular exercise), pharmacological strategies and mitochondria-targeted approaches. These strategies were mainly focused to reduce mitochondrial dysfunction and oxidative stress and to maintain mitochondrial quality in metabolic syndromes. The purpose of our article is to highlight the recent progress on the mitochondrial role in metabolic syndromes and also summarize the progress of mitochondria-targeted molecules as therapeutic targets to treat metabolic syndromes.

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Section: Mechanistic Link Between Diabetes and Oxidative Stress/mimentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in metabolic disorders — A step towards mitochondria based therapeutic strategies

Bhatti

Reddy

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

1,086

644

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“…Recognized as the most common group of inborn metabolic diseases, primary (genetic-based) mitochondrial disease has a combined minimal prevalence of at least 1 in 4,300 (Elliott et al, 2008; Gorman et al, 2015; Haas et al, 2007; Schaefer et al, 2008). In addition, RC dysfunction is broadly implicated in the pathogenesis of a host of modern-day complex diseases ranging from metabolic syndrome (Irving and Nair, 2007) to ischemia-reperfusion injury after stroke (Chouchani et al, 2014) to neurodegenerative diseases (Mandemakers et al, 2007). Regardless of cause, once RC dysfunction occurs, the effective result is the alteration of cellular NADH/NAD + redox balance that influences a wide range of cellular reactions (McCormack et al, 2015; Zhang et al, 2013), as well as the induction of both oxidative and proteotoxic stress (Segref et al, 2014).…”

Section: 1 Introductionmentioning

confidence: 99%

Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish

Byrnes

Ganetzky

Lightfoot

et al. 2018

Neurochemistry International

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Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days post fertilization also causing reduced larval survival and organ-specific defects ranging from brain death, behavioral and neurologic alterations, reduced mitochondrial membrane potential in skeletal muscle (rotenone), and/or cardiac edema with visible blood pooling (oligomycin). Remarkably, we demonstrate that treating animals with probucol, a nutrient-sensing signaling network modulating drug that has been shown to yield therapeutic effects in a range of other RC disease cellular and animal models, both prevented acute rotenone-induced brain death in zebrafish larvae, and significantly rescued early embryo developmental delay from either rotenone or oligomycin exposure. Overall, these zebrafish pharmacologic RC function inhibition models offer a unique opportunity to gain novel insights into diverse developmental, survival, organ-level, and behavioral defects of varying severity, as well as their individual response to candidate therapies, in a highly tractable and cost-effective vertebrate animal model system.

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“…Mitochondria occupy a central role in energy metabolism and regulate the programed apoptotic cell death of mammalian cells among others . A loss of their functionality can cause grievous diseases such as cancer, Alzheimer's disease, neurodegenerative disorders, and diabetes . For a better understanding of the origin of mitochondria‐related diseases, the study of key metabolic reactions is fundamental.…”

Section: Introductionmentioning

confidence: 99%

In search of an effective cell disruption method to isolate intact mitochondria from Chinese hamster ovary cells

Bahnemann

Kayo

Wahrheit

et al. 2013

Engineering in Life Sciences

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In search of an effective cell disruption method to isolate intact mitochondria from Chinese hamster ovary cellsAn efficient isolation of mitochondria from cells under physiological conditions is crucial for many studies in life sciences but still challenging in many cases such as in metabolic characterization of mitochondria. In this work, four methods for the disruption of Chinese hamster ovary cells were evaluated regarding their influence on mitochondrial integrity and yield. After cell disruption, mitochondria released from cells were separated from the remaining cell homogenate by differential centrifugation. Sonication was shown to be a rapid and sensitive isolation method. Yields of 14.0 ± 0.3 mg raw mitochondrial protein per 10 8 cells were obtained. The mitochondria were morphologically intact, with membrane integrities of 67% (outer membrane) to 94% (inner membrane). Compared with the methods using Dounce homogenization, digitonin permeabilization, or electroporation for cell disruption the ultrasound method provided the highest yield of isolated mitochondria. Furthermore, this method is rapid (≈ 45 s for disruption), more robust than Dounce homogenization regarding their influence on mitochondrial integrity and especially suitable for preparing a relatively large amount of mitochondria. The results of this work can be helpful for quantitative and dynamic studies of molecular processes related to mitochondria under physiological conditions for many questions in both biomedicine and biotechnology.

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Aging and diabetes: Mitochondrial dysfunction

Cited by 12 publications

References 30 publications

Mitochondrial dysfunction and oxidative stress in metabolic disorders — A step towards mitochondria based therapeutic strategies

Mitochondrial dysfunction and oxidative stress in metabolic disorders — A step towards mitochondria based therapeutic strategies

Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish

In search of an effective cell disruption method to isolate intact mitochondria from Chinese hamster ovary cells

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