Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species

Yu, Tianzheng; Sheu, Shey Shing; Robotham, James L.; Yoon, Yisang

doi:10.1093/cvr/cvn104

Cited by 408 publications

(391 citation statements)

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“…Insult by hyperglycemia has been shown to occur rapidly, causing mitochondrial fragmentation and increased ROS abundance within minutes of incubation with high glucose (152,153). Furthermore, observations over a time course of 24 h demonstrated cyclic fragmentation and fusion that coordinate with ROS production (152), eventually causing cell injury in later time points (153). The reported in vivo observations show representative mitochondrial morphology of the full-blown disease (20,116).…”

Section: Metabolic Insult and Mitochondrial Dynamicsmentioning

confidence: 93%

“…Another consideration in the interpretation of the in vitro data is the time point in which these experiments were conducted, monitoring cells in 24 h after treatment. Insult by hyperglycemia has been shown to occur rapidly, causing mitochondrial fragmentation and increased ROS abundance within minutes of incubation with high glucose (152,153). Furthermore, observations over a time course of 24 h demonstrated cyclic fragmentation and fusion that coordinate with ROS production (152), eventually causing cell injury in later time points (153).…”

Section: Metabolic Insult and Mitochondrial Dynamicsmentioning

confidence: 99%

“…Previously, we defined a ROS production in metabolic excess, hyperglycemic conditions, and linked their production to a coordinate observation of mitochondrial fragmentation (152,153). Inhibiting mitochondrial fission or increasing fusion normalized ROS levels in the high-glucose incubation (152).…”

Section: Metabolic Insult and Mitochondrial Dynamicsmentioning

confidence: 99%

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Mitochondrial Morphology in Metabolic Diseases

Galloway

Yoon

2013

Antioxidants & Redox Signaling

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118

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Significance: Mitochondria are the cellular energy-producing organelles and are at the crossroad of determining cell life and death. As such, the function of mitochondria has been intensely studied in metabolic disorders, including diabetes and associated maladies commonly grouped under all-inclusive pathological condition of metabolic syndrome. More recently, the altered metabolic profiles and function of mitochondria in these ailments have been correlated with their aberrant morphologies. This review describes an overview of mitochondrial fission and fusion machineries, and discusses implications of mitochondrial morphology and function in these metabolic maladies. Recent Advances: Mitochondria undergo frequent morphological changes, altering the mitochondrial network organization in response to environmental cues, termed mitochondrial dynamics. Mitochondrial fission and fusion mediate morphological plasticity of mitochondria and are controlled by membrane-remodeling mechanochemical enzymes and accessory proteins. Growing evidence suggests that mitochondrial dynamics play an important role in diabetes establishment and progression as well as associated ailments, including, but not limited to, metabolism-secretion coupling in the pancreas, nonalcoholic fatty liver disease progression, and diabetic cardiomyopathy. Critical Issues: While mitochondrial dynamics are intimately associated with mitochondrial bioenergetics, their cause-and-effect correlation remains undefined in metabolic diseases. Future Directions: The involvement of mitochondrial dynamics in metabolic diseases is in its relatively early stages. Elucidating the role of mitochondrial dynamics in pathological metabolic conditions will aid in defining the intricate form-function correlation of mitochondria in metabolic pathologies and should provide not only important clues to metabolic disease progression, but also new therapeutic targets. Antioxid. Redox Signal. 19,[415][416][417][418][419][420][421][422][423][424][425][426][427][428][429][430]

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Section: Metabolic Insult and Mitochondrial Dynamicsmentioning

confidence: 93%

Section: Metabolic Insult and Mitochondrial Dynamicsmentioning

confidence: 99%

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Mitochondrial Morphology in Metabolic Diseases

Galloway

Yoon

2013

Antioxidants & Redox Signaling

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118

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“…Cells cultured in high glucose medium displayed increased ROS levels and apoptosis, phenomenon preceded by fragmentation of the mitochondrial network, which were prevented by inhibition of mitochondrial fission (Yu et al, 2006;Yu et al, 2008).…”

Section: The Feedback Loop Between Ros Production and Mitochondrial Dmentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

140

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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“…In addition, excessive fission of mitochondria is observed in hyperglycemic conditions and this, * This work was supported, in whole or in part, by National Institutes of Health in turn, causes overproduction of reactive oxygen species, leading to apoptotic cell death (42,43). A similar event also takes place in conditions evoking high intracellular Ca 2ϩ concentrations (44 -46).…”

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confidence: 99%

Identification and Characterization of Unique Proline-rich Peptides Binding to the Mitochondrial Fission Protein hFis1

Serasinghe

Seneviratne

Smrcka

et al. 2010

Journal of Biological Chemistry

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Mammalian mitochondrial fission requires at least two proteins, hFis1 and the dynamin-like GTPase DLP1/Drp1. The mitochondrial protein hFis1 is anchored at the outer membrane by a C-terminal transmembrane domain. The cytosolic domain of hFis1 contains six ␣ helices [␣1-␣6] out of which [␣2-␣5] form tetratricopeptide repeat (TPR)-like motifs. DLP1 and possibly other proteins are thought to interact with the hFis1 TPR region during the fission process. It has also been suggested that the ␣1-helix regulates protein-protein interactions at the TPR. We performed random peptide phage display screening using the hFis1[␣2-␣6] as the target and identified ten different peptide sequences. Phage ELISA using mutant hFis1 indicates that the peptide binding requires the ␣2 and ␣3 helices and the intact TPR structure. Competition experiments and surface plasmon resonance analyses confirmed that a subset of free peptides enriched with proline residues directly bind to the target. Two of these peptides bind to the ␣1-containing intact cytosolic domain of hFis1 with decreased affinity. Peptide microinjection into cells abolished the mitochondrial swelling induced by overexpression of ␣1-deleted hFis1, and significantly decreased cytochrome c release from mitochondria upon apoptotic induction. Our data demonstrate that hFis1 can bind to multiple amino acid sequences selectively, and that the TPR constitutes the main binding region of hFis1, providing a first insight into the hFis1 TPR as a potential therapeutic target.Mitochondria are dynamic organelles that undergo constant shape changes through processes including fission and fusion of the organelle tubules (1). Mitochondrial fission and fusion are evolutionarily conserved processes, suggesting their importance in basic cell function. It is presumed that fission and fusion of mitochondria allow the mixing of the mitochondrial genome as well as other mitochondrial components such as the respiratory chain complexes to maintain adequate organelle function (2-5). Mitochondrial dynamics is also required for the proper distribution of this organelle within cells especially in neurons (6 -8) and to ensure correct inheritance of this organelle to daughter cells during cell division (9). Defects in the fission or fusion machinery result in human disease conditions, such as subtypes of Charcot-Marie-Tooth disease and autosomal dominant optic atrophy, indicating their functional importance (10 -13). In addition, abnormal phenotypes of mitochondrial morphology have been reported in several neurodegenerative diseases such as Alzheimer, Parkinson, and Huntington diseases, and recent studies indicate the direct involvement of mitochondrial fission/fusion in these diseases (14 -18).The two major processes that govern mitochondrial morphology are fission and fusion of the organelle. Studies on mitochondrial fusion in mammals have shown that dynamin-related large GTPases, mitofusin (Mfn) and OPA1, participate in the fusion of outer and inner mitochondrial membranes, respectively (19 -24). Recent ...

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Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species

Abstract: These findings indicate that the fission-mediated fragmentation of mitochondrial tubules is causally associated with enhanced production of mitochondrial ROS and cardiovascular cell injury in hyperglycaemic conditions.

Cited by 408 publications

References 49 publications

Mitochondrial Morphology in Metabolic Diseases

Mitochondrial Morphology in Metabolic Diseases

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Identification and Characterization of Unique Proline-rich Peptides Binding to the Mitochondrial Fission Protein hFis1

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