The Ins and Outs of Mitochondrial Calcium

Finkel, Toren; Menazza, Sara; Holmström, Kira M.; Parks, Randi J.; Liu, Julia; Sun, Junhui; Liu, Jie; Pan, Xin; Murphy, Elizabeth

doi:10.1161/circresaha.116.305484

Cited by 210 publications

(146 citation statements)

References 82 publications

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“…The activation of mitochondrial-derived second messengers may trigger a protective or hormetic response that provides both short-term benefits and the potential for long-term benefits in increased stress resistance and longevity (80). However, excessive activation of these pathways may ultimately become detrimental to the cell.…”

Section: +mentioning

confidence: 99%

Mitochondria in lung disease

Cloonan¹,

Choi²

2016

Journal of Clinical Investigation

207

168

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Section: +mentioning

confidence: 99%

Mitochondria in lung disease

Cloonan¹,

Choi²

2016

Journal of Clinical Investigation

207

168

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“…(13) matrix into the cytosol in exchange for glutamate (33). Ca 2ϩ from the cytoplasm also can enter the matrix via the channel called the mitochondrial Ca 2ϩ uniporter (or MCU) (64). Ca 2ϩ in the matrix lowers the K m of ␣-KGDH, the enzyme that converts ␣-KG to succinyl CoA (37).…”

Section: Control Of Metabolism By Signalingmentioning

confidence: 99%

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Rountree

Cleghorn³

et al. 2016

Journal of Biological Chemistry

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Production of energy in a cell must keep pace with demand.Photoreceptors use ATP to maintain ion gradients in darkness, whereas in light they use it to support phototransduction. Matching production with consumption can be accomplished by coupling production directly to consumption. Alternatively, production can be set by a signal that anticipates demand. In this report we investigate the hypothesis that signaling through phototransduction controls production of energy in mouse retinas. We found that respiration in mouse retinas is not coupled tightly to ATP consumption. By analyzing metabolic flux in mouse retinas, we also found that phototransduction slows metabolic flux through glycolysis and through intermediates of the citric acid cycle. We also evaluated the relative contributions of regulation of the activities of ␣-ketoglutarate dehydrogenase and the aspartate-glutamate carrier 1. In addition, a comprehensive analysis of the retinal metabolome showed that phototransduction also influences steady-state concentrations of 5-GMP, ribose-5-phosphate, ketone bodies, and purines. Warburg et al.(1) and Krebs (2) reported in the 1920s that tumors and retinas rely on aerobic glycolysis. Some of the biochemical mechanisms by which cancer cells adapt to aerobic glycolysis have been gleaned from investigations of specific metabolic adaptations of cancer cells either in culture or in a tumor (3, 4). Retinas offer distinct advantages for investigating aerobic glycolysis. They have high metabolic rates, a uniquely laminated structure, and the primary signaling pathway by which retinas respond to light is defined clearly.Retinas convert 80 -96% of glucose they consume into lactic acid (5-9), similar to the extent of aerobic glycolysis that fuels cancer cells (3). Aerobic glycolysis occurs primarily in photoreceptors (10) where the energy demands are very different in darkness than in light (5,7,(11)(12)(13). In darkness energy is consumed within the inner segments to support ion pumping (5, 13). In light energy is consumed by the outer segments (OS) 2 to support phototransduction and regeneration of visual pigments. A photoreceptor neuron also performs anabolic metabolism to replace the ϳ10% of its OS material that is lost each day to phagocytosis by the retinal pigmented epithelium (14, 15).Some of the carbons in glucose consumed by a retina reach the mitochondrial matrix where they are oxidized in biochemical reactions that reduce NAD ϩ to NADH. Transfer of electrons from NADH to O 2 then generates a proton gradient across the mitochondrial inner membrane. In some tissues dissipation of the proton gradient is coupled tightly to ATP demand. In others, proton leakage can dissipate the gradient even without ATP synthesis (16). In this report we show that mitochondria in retinas are more uncoupled than mitochondria in other tissues.The ability of a photoreceptor to respond to light, to release neurotransmitter, to regenerate visual pigment, to renew itself, and to remain viable requires that production of energy keeps pace...

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“…gen species, they are also important signaling organelles, involved in controlling apoptosis, ion homeostasis, and immune responses (1)(2)(3)(4)(5)(6). Because of their multifactorial nature, it is perhaps not surprising that mitochondria are implicated in many human diseases and age-related pathology (7)(8)(9).…”

mentioning

confidence: 99%

Mitochondrial Ribosomal Protein L12 Is Required for POLRMT Stability and Exists as Two Forms Generated by Alternative Proteolysis during Import

Nouws¹,

Goswami²,

Bestwick

et al. 2016

Journal of Biological Chemistry

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To translate the 13 mtDNA-encoded mRNAs involved in oxidative phosphorylation (OXPHOS), mammalian mitochondria contain a dedicated set of ribosomes comprising rRNAs encoded by the mitochondrial genome and mitochondrial ribosomal proteins (MRPs) that are encoded by nuclear genes and imported into the matrix. In addition to their role in the ribosome, several MRPs have auxiliary functions or have been implicated in other cellular processes like cell cycle regulation and apoptosis. For example, we have shown that human MRPL12 binds and activates mitochondrial RNA polymerase (POLRMT), and hence has distinct functions in the ribosome and mtDNA transcription. Here we provide concrete evidence that there are two mature forms of mammalian MRPL12 that are generated by a two-step cleavage during import, involving efficient cleavage by mitochondrial processing protease and a second inefficient or regulated cleavage by mitochondrial intermediate protease.We also show that knock-down of MRPL12 by RNAi results in instability of POLRMT, but not other primary mitochondrial transcription components, and a corresponding decrease in mitochondrial transcription rates. Knock-down of MRPL10, the binding partner of MRPL12 in the ribosome, results in selective degradation of the mature long form of MRPL12, but has no effect on POLRMT. We propose that the two forms of MRPL12 are involved in homeostatic regulation of mitochondrial transcription and ribosome biogenesis that likely contribute to cell cycle, growth regulation, and longevity pathways to which MRPL12 has been linked.

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The Ins and Outs of Mitochondrial Calcium

Cited by 210 publications

References 82 publications

Mitochondria in lung disease

Mitochondria in lung disease

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Mitochondrial Ribosomal Protein L12 Is Required for POLRMT Stability and Exists as Two Forms Generated by Alternative Proteolysis during Import

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