Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

Tubbs, Emily; Rieusset, Jennifer

doi:10.1530/jme-16-0189

Cited by 94 publications

(81 citation statements)

References 132 publications

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“…In contrast, outer mitochondrial fusion is mediated by two dynamin-related GTPases, mitofusins 1 and mitofusin 2 (Mfn1/2), which can interact both homo- and hetero-typically to mediate mitochondrial fusion. Mfn2 has also been recently demonstrated to serve an additional role of mitochondrial tethering to the endoplasmic reticulum, facilitating interorganelle cross talk and calcium signaling (5). Inner membrane fusion and cristae stabilization, on the other hand, involves another dynamin-related GTPase, Opa1 (optic atrophy 1).…”

Section: Mitochondrial Dynamicsmentioning

confidence: 99%

The hallmarks of mitochondrial dysfunction in chronic kidney disease

Galvan

Green

Danesh

2017

Kidney International

345

305

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Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to diverse acute and chronic pathologies. Indeed, mitochondria have received increasing attention as a therapeutic target in a variety of diseases since they serve as key regulatory hubs uniquely situated at crossroads between multiple cellular processes. This review provides an overview of the role of mitochondrial dysfunction in chronic kidney disease (CKD) with special emphasis on its role in the development of diabetic nephropathy (DN). We will examine the current understanding on the molecular mechanisms that cause mitochondrial dysfunction in the kidney and describe the impact of mitochondrial damage on kidney function. The new concept that mitochondrial shape and structure is intimately linked with its function in the kidneys is discussed. Furthermore, the mechanisms that translate cellular cues and demands into mitochondrial remodeling and cellular damage, including the role of microRNAs and lncRNAs, are examined with the final goal of identifying mitochondrial targets to improve treatment of patients with chronic kidney diseases.

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Section: Mitochondrial Dynamicsmentioning

confidence: 99%

The hallmarks of mitochondrial dysfunction in chronic kidney disease

Galvan

Green

Danesh

2017

Kidney International

345

305

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“…Currently two findings support the function of the MCU under physiological conditions. First, the Ca 2+ level at the SR-mitochondria junctions is high enough to trigger MCU-mediated Ca 2+ influx (Rizzuto et al 1998;Tubbs & Rieusset, 2017). Second, the MCU is located at these junctions and in close proximity to the SR Ca 2+ release channel, RyR2, in cardiomyocytes (De La Fuente et al 2016).…”

Section: Other Mitochondrial Ca 2+ Handling Mechanisms May Regulate Ementioning

confidence: 99%

Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?

Wang

Fernandez-Sanz

Wang

et al. 2018

The Journal of Physiology

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Current dogma holds that the heart balances energy demand and supply effectively and sustainably by sequestering enough Ca into mitochondria during heartbeats to stimulate metabolic enzymes in the tricarboxylic acid (TCA) cycle and electron transport chain (ETC). This process is called excitation-contraction-bioenergetics (ECB) coupling. Recent breakthroughs in identifying the mitochondrial Ca uniporter (MCU) and its associated proteins have opened up new windows for interrogating the molecular mechanisms of mitochondrial Ca homeostasis regulation and its role in ECB coupling. Despite remarkable progress made in the past 7 years, it has been surprising, almost disappointing, that germline MCU deficiency in mice with certain genetic background yields viable pups, and knockout of the MCU in adult heart does not cause lethality. Moreover, MCU deficiency results in few adverse phenotypes, normal performance, and preserved bioenergetics in the heart at baseline. In this review, we briefly assess the existing literature on mitochondrial Ca homeostasis regulation and then we consider possible explanations for why MCU-deficient mice are spared from energy crises under physiological conditions. We propose that MCU and/or mitochondrial Ca may have limited ability to set ECB coupling, that other mitochondrial Ca handling mechanisms may play a role, and that extra-mitochondrial Ca may regulate ECB coupling. Since the heart needs to regenerate a significant amount of ATP to assure the perpetuation of heartbeats, multiple mechanisms are likely to work in concert to match energy supply with demand.

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“…Recent findings have shown the roles of small peptides as drug active agents that can modulate the physiological functions for the prevention of diabetes. The present study reports the preventive effects of small peptides in mice exposed to diabetes by hormonal (insulin and GLP‐1) and enzymatic (DPP‐4) communications involved in glucose homeostasis.…”

Section: Discussionmentioning

confidence: 78%

Leucine–glycine and carnosine dipeptides prevent diabetes induced by multiple low‐doses of streptozotocin in an experimental model of adult mice

Vahdatpour

Nokhodchi

Zakeri–Milani

et al. 2019

J of Diabetes Invest

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Aims/Introduction Peptides are considered to be quasi‐hormones and effective molecules for regulation of the cells function and prevention of metabolic disorders. Di‐ and tripeptides gastrointestinal absorption ability have been proposed to prevent diabetes progression. Materials and Methods Small peptides with different sequences of specific amino acids were synthesized based on a solid phase peptide synthesis protocol, and carnosine (A) and glutathione were examined for the prevention of diabetes induced by multiple low‐doses of streptozotocin in mice. Results The peptides A, Leu‐Gly (D) and Pro‐Pro showed preventive effects on blood glucose elevation and impairment of the signaling and performance of β‐cells. The β‐cell function assessed by immunofluorescence and blood glucose level in mice exposed to diabetes treated by the peptides A and D was similar to the normal mice. The peptide D prevented bodyweight loss caused by diabetes induction. The use of D and A peptides dramatically prevented the incidence of disruption in β‐cells signaling by maintaining the natural balance of intracellular Akt‐2 and cyclic adenosine monophosphate. Conclusions The results proved that peptide D (Leu‐Gly), named Hannaneh, inhibits the bodyweight loss caused by diabetes induction. The Hannaneh and carnosine dipeptides, with preservation of normal β‐cell signaling and anti dipeptidyl peptidase‐4 activity, prevented blood glucose increases in mice at risk of diabetes. These dipeptides might be regarded as the pharmaceutical agents for the prevention of diabetes.

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Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

Cited by 94 publications

References 132 publications

The hallmarks of mitochondrial dysfunction in chronic kidney disease

The hallmarks of mitochondrial dysfunction in chronic kidney disease

Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?

Leucine–glycine and carnosine dipeptides prevent diabetes induced by multiple low‐doses of streptozotocin in an experimental model of adult mice

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Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

Cited by 94 publications

References 132 publications

The hallmarks of mitochondrial dysfunction in chronic kidney disease

The hallmarks of mitochondrial dysfunction in chronic kidney disease

Why don't mice lacking the mitochondrial Ca2+ uniporter experience an energy crisis?

Leucine–glycine and carnosine dipeptides prevent diabetes induced by multiple low‐doses of streptozotocin in an experimental model of adult mice

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Why don't mice lacking the mitochondrial Ca²⁺ uniporter experience an energy crisis?