The Pyruvate Dehydrogenase Complexes: Structure-based Function and Regulation

Patel, Mulchand S.; Nemeria, Natalia S.; Furey, W.; Jordan, Frank

doi:10.1074/jbc.r114.563148

Cited by 449 publications

(397 citation statements)

References 97 publications

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“…2 and 3). The rate-limiting step in mitochondrial carbohydrate metabolism is carried out by the PDC, a multiprotein complex that catalyzes the oxidative decarboxylation of pyruvate (24). We found that several components of the PDC, namely the catalytic pyruvate dehydrogenase PDH-E1β (Pdhb), PDH-E2 (Dlat), and the regulatory subunit PDHX (Pdhx), accumulate in a daily manner with maximum levels at ∼ZT3 ( Fig.…”

Section: Quantitative Proteomics Identify a Predominant Daily Phase Formentioning

confidence: 97%

Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Neufeld-Cohen

Robles

Aviram

et al. 2016

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

197

192

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Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization.M itochondria serve as major suppliers of cellular energy through nutrient oxidation. One of the major challenges that mitochondria face is the adaptation to changes in nutrient supply and energy demand. An inability of mitochondria to deal with altered nutrient environment is associated with metabolic diseases, such as diabetes and obesity (1, 2).Mitochondria oxidize carbohydrates and lipids to generate ATP by a process known as oxidative phosphorylation. Pyruvate and fatty acids are transported from the cytoplasm into the mitochondrial matrix, where they are catabolized into acetyl CoA. Pyruvate is converted to acetyl CoA through the action of the pyruvate dehydrogenase complex (PDC), whereas fatty acids are oxidized through a cycle of reactions that trim two carbons at a time, generating one molecule of acetyl CoA in each cycle [i.e., fatty acid oxidation (FAO)]. The acetyl groups are then fed into the Krebs cycle for additional degradation, and the process culminates with the transfer of acetyl-derived high-energy electrons along the respiratory chain.Mounting evidence suggests that circadian clocks orchestrate our daily physiology and metabolism (3-6). The mammalian circadian timing system consists of a central pacemaker in the brain that is entrained by daily light-dark cycles and synchronizes subsidiary oscillators in virtually all cells of the body, in part by driving rhythmic feeding behavior. The core clock molecular circuitry relies on interlocked transcription-translation feedback loops that generate daily oscillations of gene expression in cultured cells and living animals (7). Many transcriptomes (8-12) and more recently, several proteomics (13-15) and metabolomics studies (16-21) highlighted the pervasive circadian control of metabolism.Rest-activity and feeding-fasting cycles that naturally occur throughout the day impose pronounced changes in nutrient s...

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Section: Quantitative Proteomics Identify a Predominant Daily Phase Formentioning

confidence: 97%

Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Neufeld-Cohen

Robles

Aviram

et al. 2016

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

197

192

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“…Taken together, Pdks play an essential role in regulating pyruvate entry into the TCA cycle. Moreover, phosphorylated PDH-E1α subunit is dephosphorylated by pyruvate dehydrogenase phosphatase (Pdp) [22]. Thus, reversible regulation of PDH activity by Pdks and Pdp enables finetuning of metabolic flux from glycolysis to the TCA cycle in various cellular states.…”

Section: Pdh Regulation Of Metabolite Flux Into the Tca Cyclementioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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“…The pyruvate dehydrogenase complex (PDC) catalyzes oxidative decarboxylation of pyruvate into acetyl-CoA, which is subsequently used in Krebs cycle to generate ATP (110,118). PDC plays a key role in glucose metabolism, linking glycolysis with the Krebs cycle.…”

Section: Sirt3 Deacetylates Pdc E1a To Promote Glucose Oxidationmentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

123

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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The Pyruvate Dehydrogenase Complexes: Structure-based Function and Regulation

Cited by 449 publications

References 97 publications

Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

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