High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy

Gomes, Lígia C.; Scorrano, Luca

doi:10.1016/j.bbabio.2008.05.442

Cited by 216 publications

(146 citation statements)

References 60 publications

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“…Recently, strong activation of autophagosome formation by hFis1 overexpression has been demonstrated in mouse fibroblasts, which correlated with mitochondrial dysfunction rather than with fragmentation (44). Fragmentation per se is not sufficient to trigger autophagy, which could explain why the mitochondrial volume was selectively decreased in hFis1-overexpressing cells.…”

Section: Discussionmentioning

confidence: 99%

Selective Actions of Mitochondrial Fission/Fusion Genes on Metabolism-Secretion Coupling in Insulin-releasing Cells

Park¹,

Wiederkehr²,

Kirkpatrick³

et al. 2008

Journal of Biological Chemistry

104

106

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Mitochondria form filamentous networks that undergo continuous fission/fusion. In the pancreatic ␤-cells, mitochondria are essential for the transduction of signals linking nutrient metabolism to insulin granule exocytosis. Here we have studied mitochondrial networks in the insulinoma cell line INS-1E, primary rat and human ␤-cells. We have further investigated the impact of mitochondrial fission/fusion on metabolism-secretion coupling in INS-1E cells. Overexpression of hFis1 caused dramatic mitochondrial fragmentation, whereas Mfn1 evoked hyperfusion and the aggregation of mitochondria. Cells overexpressing hFis1 or Mfn1 showed reduced mitochondrial volume, lowered cellular ATP levels, and as a consequence, impaired glucose-stimulated insulin secretion. Decreased mitochondrial ATP generation was partially compensated for by enhanced glycolysis as indicated by increased lactate production in these cells. Dominant-negative Mfn1 elicited mitochondrial shortening and fragmentation of INS-1E cell mitochondria, similar to hFis1. However, the mitochondrial volume, cytosolic ATP levels, and glucose-stimulated insulin secretion were little affected. We conclude that mitochondrial fragmentation per se does not impair metabolism-secretion coupling. Through their impact on mitochondrial bioenergetics and distribution, hFis1 and Mfn1 activities influence mitochondrial signal generation thereby insulin exocytosis.

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Section: Discussionmentioning

confidence: 99%

Selective Actions of Mitochondrial Fission/Fusion Genes on Metabolism-Secretion Coupling in Insulin-releasing Cells

Park¹,

Wiederkehr²,

Kirkpatrick³

et al. 2008

Journal of Biological Chemistry

104

106

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“…Earlier studies have shown that FIS1 overexpression promotes mitochondrial fragmentation, whereas FIS1 depletion produces interconnected mitochondrial nets (62,63). Furthermore, overexpression of F1S1 has been reported to cause autophagy (64). Similarly DNM1 was identified in search of genes required for mitophagy as the dnm1⌬ strain has been found to inhibit mitophagy (65,66).…”

Section: Discussionmentioning

confidence: 99%

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

Kumar¹,

John

Maity

et al. 2011

Journal of Biological Chemistry

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An elevated level of homocysteine, a thiol amino acid, is associated with various complex disorders. The cellular effects of homocysteine and its precursors S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) are, however, poorly understood. We used Saccharomyces cerevisiae as a model to understand the basis of pathogenicity induced by homocysteine and its precursors. Both homocysteine and AdoHcy but not AdoMet inhibited the growth of the str4⌬ strain (which lacks the enzyme that converts homocysteine to cystathioninemimicking vascular cells). Addition of AdoMet abrogated the inhibitory effect of AdoHcy but not that of homocysteine indicating that an increase in the AdoMet/AdoHcy ratio is sufficient to overcome the AdoHcy-mediated growth defect but not that of homocysteine. Also, the transcriptomic profile of AdoHcy and homocysteine showed gross dissimilarity based on gene enrichment analysis. Furthermore, compared with homocysteine, AdoHcy treatment caused a higher level of oxidative stress in the cells. However, unlike a previously reported response in wild type (Kumar, A., John, L., Alam, M. M., Gupta, A., Sharma, G., Pillai, B., and Sengupta, S. (2006) Biochem. J. 396, 61-69), the str4⌬ strain did not exhibit an endoplasmic reticulum stress response. This suggests that homocysteine induces varied response depending on the flux of homocysteine metabolism. We also observed altered expression of mitochondrial genes, defective membrane potential, and fragmentation of the mitochondrial network together with the increased expression of fission genes indicating that the imbalance in homocysteine metabolism has a major effect on mitochondrial functions. Furthermore, treatment of cells with homocysteine or AdoHcy resulted in apoptosis as revealed by annexin V staining and TUNEL assay. Cumulatively, our results suggest that elevated levels of homocysteine lead to mitochondrial dysfunction, which could potentially initiate pro-apoptotic pathways, and this could be one of the mechanisms underlying homocysteineinduced pathogenicity.

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“…So far, mitophagy has been associated with a loss of mitochondrial membrane potential and a transient increase in UCP3 levels upon lipopolysaccharide exposure [84], the appearance of mitochondrial ROS [83,[85][86][87], ionic imbalances [88] and high levels of mitochondrial fission protein 1 [89]. Thus, mitophagy has been causally associated with phenomena that are also reported as a consequence of lipotoxicity, indicating lipotoxicity as a feasible initiator of mitophagic processes.…”

Section: Mitophagy As a Potential Endpoint Of Lipotoxic Changes Aftermentioning

confidence: 99%

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

Graier

Malli

Kostner

2009

Trends in Endocrinology & Metabolism

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Lipotoxicity occurs as a consequence of chronic exposure of non-adipose tissue and cells to elevated concentrations of fatty acids, triglycerides and/or cholesterol. The contribution of mitochondria to lipotoxic cell dysfunction, damage and death is associated with elevated production of reactive oxygen species and initiation of apoptosis. Although there is a broad consensus on the involvement of these phenomena with lipotoxicity, the molecular mechanisms that initiate, mediate and trigger mitochondrial dysfunction in response to substrate overload remain unclear. Here, we focus on protein phosphorylation as an important phenomenon in lipotoxicity that harms mitochondria-related signal transduction and integration in cellular metabolism. Moreover, the degradation of mitochondria by mitophagy is discussed as an important landmark that leads to cellular apoptosis in lipotoxicity. Mitochondrial relay functionThe term 'lipotoxicity' describes the dysfunction of non-adipose tissue and cells that face chronic exposure to elevated fatty acids, triglycerides and/or cholesterol [1][2][3]. When plasma levels of prandial and postprandial fatty acids, triglycerides or cholesterol exceed the uptake capacity of adipose tissue, non-adipose tissue becomes overloaded with lipids, resulting in several metabolic imbalances and/or diseases. Once the oxidative capacity of these cells is exhausted, lipotoxic pathways are initiated that yield cellular dysfunction and, at worst, result in cell death. Although multiple lipotoxic events have been described [1][2][3] (e.g. induction of endoplasmic reticulum stress [4,5] by disruption of its structural integrity [6]) recent findings point to mitochondrial dysfunction as a key phenomenon in lipotoxicity leading to ominous signals [7][8][9][10][11].The mitochondria not only serve as the power plant of the cell but also act as a cellular relay, sensing multiple cellular and environmental parameters, including energy status, oxygen availability and activation patterns of cellular signal-transduction pathways. Mitochondria then integrate these inputs, adapting their activity and functions to, ultimately, tune cellular responsiveness with respect to the current demand of the cell [12] (Figure 1). In spite of the important tasks of the mitochondrion and in contrast to its functions in energy metabolism, its contribution to signal transduction has not been thoroughly investigated, and the [24,25]. Because similar pathways were also described as leading to cellular differentiation [17], the actual physiological outcome might depend on the pattern of activated pathways rather than on a single phenomenon. Thus, it is feasible that changes in the mitochondrial phosphoproteome caused by alterations in kinase activities are fundamental for the decisive setting of signaling patterns for cell survival or the initiation of cellular dysfunction in lipotoxicity leading to cell death. Three different scenarios affecting mitochondrial protein phosphorylation can be postulated in lipotoxicity ( Figure ...

show abstract

High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy

Cited by 216 publications

References 60 publications

Selective Actions of Mitochondrial Fission/Fusion Genes on Metabolism-Secretion Coupling in Insulin-releasing Cells

Selective Actions of Mitochondrial Fission/Fusion Genes on Metabolism-Secretion Coupling in Insulin-releasing Cells

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

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