Mitochondrial acetylcarnitine provides acetyl groups for nuclear histone acetylation

Madiraju, Padma; Pande, Shri V.; Prentki, Marc; Madiraju, S.R. Murthy

doi:10.4161/epi.4.6.9767

Cited by 117 publications

(91 citation statements)

References 15 publications

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“…Acetylation/ deacetylation reactions thus modulate cell signaling pathways and gene expression (137,160). To the authors' knowledge, besides one study (95), data demonstrating direct mitochondrial signaling by Ac-CoA is lacking. However, changes in the production and export of Ac-CoA by mitochondria could theoretically impact cellular function.…”

Section: R399 Mitochondrial Morphology and Functionmentioning

confidence: 99%

“…In the cytosol, Ac-CoA acts as substrate for lysine acetylation by protein acetyltransferases (137). Some evidence suggests that mitochondrial acetylcarnitine, a derivative of Ac-CoA, is exported to the cytoplasm by carnitine/acylcarnitine translocase where it can enter the nucleus and be converted back to AcCoA to act as source of acetyl group for histone acetylation (95). Like protein phosphorylation, acetylation and deacetylation (by NAD ϩ -dependent deacetylases) are function-defining posttranslational modifications regulating the function of numerous proteins, including membrane-associated receptors, transcriptional coactivators and transcription factors, and histones involved in chromatin remodeling (137,160).…”

Section: R399 Mitochondrial Morphology and Functionmentioning

confidence: 99%

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Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Picard

Shirihai

Gentil

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

264

193

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In response to cellular and environmental stresses, mitochondria undergo morphology transitions regulated by dynamic processes of membrane fusion and fission. These events of mitochondrial dynamics are central regulators of cellular activity, but the mechanisms linking mitochondrial shape to cell function remain unclear. One possibility evaluated in this review is that mitochondrial morphological transitions (from elongated to fragmented, and vice-versa) directly modify canonical aspects of the organelle's function, including susceptibility to mitochondrial permeability transition, respiratory properties of the electron transport chain, and reactive oxygen species production. Because outputs derived from mitochondrial metabolism are linked to defined cellular signaling pathways, fusion/fission morphology transitions could regulate mitochondrial function and retrograde signaling. This is hypothesized to provide a dynamic interface between the cell, its genome, and the fluctuating metabolic environment. mitochondrial dynamics; morphology; fusion and fission; bioenergetics; retrograde signaling MITOCHONDRIA are crucial organelles involved in cellular energy production and in the regulation of numerous aspects of cellular activity, including, but not limited to, apoptosis, Ca 2ϩ signaling, and redox homeostasis (41). Over the last decade, mitochondria have moved to the forefront of cell biology research for their ability to undergo regulated events of membrane fusion and fission, which remodel the architecture of the mitochondrial network within the cytoplasm (43,36,146). Processes of mitochondrial fusion and fission are collectively termed mitochondrial dynamics. Importantly, abnormal mitochondrial dynamics cause bioenergetic defects (26), induce embryonic lethality in transgenic animal models (27), and underly a heterogenous group of human diseases (164), attesting to the pivotal role of these processes in physiopathology (25,50,91). In addition, experimental work has shown that mitochondrial dynamics are involved in regulating cellular activity and that mitochondria participate in important cellular signaling pathways (136,158).Mitochondrial retrograde signaling is defined as the transfer of information from mitochondria to the cytoplasm and nucleus. Retrograde signaling pathways have been established to occur in response to metabolic perturbations, with the aim to trigger adaptive cellular responses orchestrated by coordinated changes in gene expression (reviewed in Refs. 21 and 93). Among the retrograde signals produced by mitochondria that are known to regulate different aspects of cellular activity, the most studied include reactive oxygen species (ROS), pro-apoptotic molecules, ATP/ADP/AMP, metabolic intermediates (NAD ϩ /NADH), and Ca 2ϩ (20,39,58). From recent discoveries revealing that mitochondrial dynamics regulate cellular activity in response to various stressors, it is hypothesized that changes in mitochondrial morphology regulate, either directly or indirectly, various aspects of mitochondrial funct...

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Section: R399 Mitochondrial Morphology and Functionmentioning

confidence: 99%

Section: R399 Mitochondrial Morphology and Functionmentioning

confidence: 99%

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Picard

Shirihai

Gentil

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

264

193

View full text Add to dashboard Cite

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“…Mitochondrial acetyl-CoA can also be exported out of the mitochondrion as acetylcarnitine by the carnitine/acylcarnitine acetyltranslocase. In the cytosol, acetylcarnitine reverts back into acetylCoA for use in histone acetylation (41).…”

Section: Energy Fluctuation and Cyclic Adaptationmentioning

confidence: 99%

Bioenergetics, the origins of complexity, and the ascent of man

Wallace

2010

Proc. Natl. Acad. Sci. U.S.A.

117

109

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Complex structures are generated and maintained through energy flux. Structures embody information, and biological information is stored in nucleic acids. The progressive increase in biological complexity over geologic time is thus the consequence of the informationgenerating power of energy flow plus the information-accumulating capacity of DNA, winnowed by natural selection. Consequently, the most important component of the biological environment is energy flow: the availability of calories and their use for growth, survival, and reproduction. Animals can exploit and adapt to available energy resources at three levels. They can evolve different anatomical forms through nuclear DNA (nDNA) mutations permitting exploitation of alternative energy reservoirs, resulting in new species. They can evolve modified bioenergetic physiologies within a species, primarily through the high mutation rate of mitochondrial DNA (mtDNA)-encoded bioenergetic genes, permitting adjustment to regional energetic environments. They can alter the epigenomic regulation of the thousands of dispersed bioenergetic genes via mitochondrially generated high-energy intermediates permitting individual accommodation to short-term environmental energetic fluctuations. Because medicine pertains to a single species, Homo sapiens, functional human variation often involves sequence changes in bioenergetic genes, most commonly mtDNA mutations, plus changes in the expression of bioenergetic genes mediated by the epigenome. Consequently, common nDNA polymorphisms in anatomical genes may represent only a fraction of the genetic variation associated with the common "complex" diseases, and the ascent of man has been the product of 3.5 billion years of information generation by energy flow, accumulated and preserved in DNA and edited by natural selection.C harles Darwin and Albert Russel Wallace hypothesized that the environment acts on individual variation via natural selection to create new species (1, 2). However, nothing in the concept of natural selection requires that biological systems should evolve toward ever greater complexity. Yet, throughout the more than 3.5 billion years of biological evolution (3), life has generated ever more complex forms. What, then, drives increasing biological complexity, and what are its implications for the ascent of man? Bioenergetics and the Origin of Biological ComplexityIn a thermodynamically isolated system, complex structures decay toward randomness. However, in nonequilibrium systems, the flow of energy through the system generates and sustains structural complexity, and nonhomogeneous structures embody information (4, 5).On Earth, the flux of energy through the biosphere is relatively constant. If the flow of energy were the only factor generating complexity, complexity would soon achieve a steady state between the production and decay of structure. Biology is not static, because the information embedded in biological structures can be encoded and duplicated by informational molecules, DNA and RNA. Therefore, bio...

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“…Based on the observation that ALC provides acetyl groups for protein acetylation (5,6), it is conceivable that ALC may have a cooperative effect with HDAC inhibitors. It is well known that the acetylation of critical proteins mediated by HDAC6 is involved in the regulation of the malignant behavior of tumor cells, particularly in the metastatic process (17,18).…”

Section: Antimetastatic Efficacy Of the Alc Combination With A Hdac Imentioning

confidence: 99%

“…This function, mediated by carnitine acetyl transferase, is relevant for mitochondrial energy production and other biosynthetic processes (3). At the nuclear level, ALC provides a source of acetyl groups for nuclear protein acetylation by histone acetyl-transferases (6). Acetylation of the transcription factor p53 by histone acetyl transferase p300/CBP has been reported to enhance its transcriptional activity (7).…”

mentioning

confidence: 99%

Metabolic Approach to the Enhancement of Antitumor Effect of Chemotherapy: a Key Role of Acetyl-l-Carnitine

Pisano

Vesci

Milazzo

et al. 2010

Clinical Cancer Research

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Purpose: Acetyl-L-carnitine (ALC) plays a relevant role in energy metabolism and stress response because of its function in the complex metabolic system regulating the acetyl-CoA levels that provide a source of acetyl groups for metabolic and acetylation-regulated processes. Because acetylation may influence p53 activity/stability and, therefore, the response to platinum compounds, this study was designed to investigate the effect of ALC in combination with platinum compounds.Experimental Design: The antiproliferative and antitumor activity studies were done in a panel of human tumor cell lines with functional or defective p53. The antimetastatic drug efficacy was investigated in the s.c. growing H460/M tumor subline, which is able to generate lung metastases.Results: ALC enhanced the sensitivity to cisplatin of tumor cells with functional p53. The sensitization by ALC was reflected in an improved in vivo antitumor efficacy of the combination over cisplatin alone in wild-type p53 lung tumors. ALC did not increase the cisplatin efficacy in the p53-mutant SW620 tumor. ALC exhibited a significant antimetastatic activity, and this effect was better exploited in combination with the histone deacetylase inhibitor, ST3595. The in vivo ALC/cisplatin combination caused the activation of p53, associated with protein acetylation and induction of target genes.Conclusions: ALC was effective in enhancing the antitumor potential of platinum compounds in wildtype p53 tumors. ALC, alone and in combination with a histone deacetylase inhibitor, exhibited an outstanding antimetastatic activity. Both effects, likely mediated by protein acetylation, may have implications for platinum-based therapy and combinations with histone deacetylase inhibitors. Clin Cancer Res; 16(15); 3944-53. ©2010 AACR.

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Mitochondrial acetylcarnitine provides acetyl groups for nuclear histone acetylation

Cited by 117 publications

References 15 publications

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Mitochondrial morphology transitions and functions: implications for retrograde signaling?

Bioenergetics, the origins of complexity, and the ascent of man

Metabolic Approach to the Enhancement of Antitumor Effect of Chemotherapy: a Key Role of Acetyl-l-Carnitine

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