Mitochondrial Biogenesis in Mammals: The Role of Endogenous Nitric Oxide

Nisoli, Enzo; Clementi, Emilio; Paolucci, Clara; Cozzi, Valeria; Tonello, Cristina; Sciorati, Clara; Bracale, Renata; Valerio, Alessandra; Francolini, Maura; Moncada, Salvador; Carruba, Michele O.

doi:10.1126/science.1079368

Cited by 1,112 publications

(991 citation statements)

References 20 publications

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“…Exactly how mitochondrial deficiency is caused in CGNs of old mutant mice is unclear and warrants further study. At least one of the consequences of reduced nitric oxide signaling is reduced mitochondrial biogenesis, because nitric oxide signaling is necessary for mitochondrial biogenesis (Nisoli et al ., 2003). Either increased peroxynitrite production, reduced nitric oxide signaling, or both could contribute to mitochondrial deficiency and CGN degeneration (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Liu

Lü

2015

Aging Cell

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SummaryReactive oxygen species are implicated in age‐associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2‐like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age‐associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria‐targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age‐matched normal control mice or SkQ1‐treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4‐hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age‐associated neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Liu

Lü

2015

Aging Cell

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“…This could be explained by downregulation of upstream genes such as transcription co-activator factors that modulate expression of nuclear and/or mitochondrial DNA (Lehman et al, 2000;Molkentin and Dorn, 2001;Nisoli et al, 2003). Indeed, a significant decrease in the expression of transcription coactivator factor genes coding for PGC-1α, PGC-1β, PPAR-δ, ERR-γ, nuclear factor erythroidderived 2-like 1 and nuclear factor erythroid-derived 2-like 2, which modulates gene expression of enzymes regulating mitochondrial metabolism and mitogenesis (Lin et al, 2005) was observed in the senescent heart ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

Preston¹,

Oberlin²,

Holmuhamedov³

et al. 2008

Mechanisms of Ageing and Development

120

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Aging is associated with progressive decline in energetic reserves compromising cardiac performance and tolerance to injury. Although deviations in mitochondrial functions have been documented in senescent heart, the molecular bases for the decline in energy metabolism are only partially understood. Here, high-throughput transcription profiles of genes coding for mitochondrial proteins in ventricles from adult (6-months) and aged (24-months) rats were compared using microarrays. Out of 614 genes encoding for mitochondrial proteins, 94 were differentially expressed with 95% downregulated in the aged. The majority of changes affected genes coding for proteins involved in oxidative phosphorylation (39), substrate metabolism (14) and tricarboxylic acid cycle (6). Compared to adult, gene expression changes in aged hearts translated into a reduced mitochondrial functional capacity, with decreased NADH-dehydrogenase and F0F1-ATPase complex activities and capacity for oxygen-utilization and ATP synthesis. Expression of genes coding for transcription co-activator factors involved in the regulation of mitochondrial metabolism and biogenesis were downregulated in aged ventricles without reduction in mitochondrial density. Thus, aging induces a selective decline in activities of oxidative phosphorylation complexes I and V within a broader transcriptional downregulation of mitochondrial genes, providing a substrate for reduced energetic efficiency associated with senescence.

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“…This operates through the cGMP-dependent peroxisome proliferator-activating receptor γ coactivator-1α, a master regulator of mitochondrial biogenesis [41]. NO was shown to induce mitochondrial biogenesis in brown adipocytes, U937 and HeLa cells and human lymphocytes [42,43]. Studies of T lymphocytes lacking eNOS will be important to establish an absolute requirement of this NOS isoform in T-cell activation.…”

Section: Role Of Nitric Oxide In T Cell Activation Mitochondrial Biomentioning

confidence: 99%

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

Nagy

Koncz

Fernández

et al. 2007

Free Radical Biology and Medicine

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T lymphocyte activation is associated with nitric oxide (NO) production that plays an essential role in multiple T cell functions. NO acts as a messenger, activating soluble guanyl cyclase and participating in the transduction signaling pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial membrane potential and mitochondrial biogenesis in many cell types, including lymphocytes. Mitochondrial hyperpolarization (MHP), an early and reversible event during both T lymphocyte activation and apoptosis, is regulated by NO. Here, we discuss recent evidence that NO-induced MHP represents a molecular switch in multiple T cell signaling pathways. Overproduction of NO in systemic lupus erythematosus (SLE) induces mitochondrial biogenesis and alters Ca 2+ signaling. Thus, while NO plays a physiological role in lymphocyte cell signaling, its overproduction may disturb normal T cell function, contributing to the pathogenesis of autoimmunity.

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Mitochondrial Biogenesis in Mammals: The Role of Endogenous Nitric Oxide

Cited by 1,112 publications

References 20 publications

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

The Immp2l mutation causes age‐dependent degeneration of cerebellar granule neurons prevented by antioxidant treatment

Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart

Nitric oxide, mitochondrial hyperpolarization, and T cell activation☆

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