Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT)

Pharaoh, Gavin; Kamat, Varun; Kannan, Sricharan; Stuppard, Rudolph; Whitson, Jeremy; Martín-Pérez, Miguel; Qian, Weijun; MacCoss, Michael J.; Villén, Judit; Rabinovitch, Peter S.; Campbell, Matthew; Sweet, Ian R.; Marcinek, David J.

doi:10.1101/2023.02.01.525989

Cited by 3 publications

(3 citation statements)

References 39 publications

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“…This leads to increased production of supercomplexes, greater membrane stability, reducing ROS levels and elevating ATP synthesis (Karaa et al, 2023). Elamipretide treatment was also shown to increase ADP sensitivity in vivo and decrease ROS production in vitro (Pharaoh et al, 2023). This has led to clinical trials investigating the potential therapeutic effect of elamipretide.…”

Section: Elamipretidementioning

confidence: 97%

“…Elamipretide (ELAM, SS-31, Bendavia, ELViS-FA, MTP-131) is a mitochondria-targeted peptide, capable of localising to the inner mitochondrial membrane (IMM) where it associates with cardiolipin and modulates mitochondria function (ClinicalTrials, 2022;Karaa et al, 2023;Pharaoh et al, 2023). This leads to increased production of supercomplexes, greater membrane stability, reducing ROS levels and elevating ATP synthesis (Karaa et al, 2023).…”

Section: Elamipretidementioning

confidence: 99%

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Emerging antioxidant therapies in Friedreich’s ataxia

Edzeamey,

Ramchunder,

Pourzand

et al. 2024

Front. Pharmacol.

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Friedreich’s ataxia (FRDA) is a rare childhood neurologic disorder, affecting 1 in 50,000 Caucasians. The disease is caused by the abnormal expansion of the GAA repeat sequence in intron 1 of the FXN gene, leading to the reduced expression of the mitochondrial protein frataxin. The disease is characterised by progressive neurodegeneration, hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. The reduced expression of frataxin has been suggested to result in the downregulation of endogenous antioxidant defence mechanisms and mitochondrial bioenergetics, and the increase in mitochondrial iron accumulation thereby leading to oxidative stress. The confirmation of oxidative stress as one of the pathological signatures of FRDA led to the search for antioxidants which can be used as therapeutic modality. Based on this observation, antioxidants with different mechanisms of action have been explored for FRDA therapy since the last two decades. In this review, we bring forth all antioxidants which have been investigated for FRDA therapy and have been signed off for clinical trials. We summarise their various target points in FRDA disease pathway, their performances during clinical trials and possible factors which might have accounted for their failure or otherwise during clinical trials. We also discuss the limitation of the studies completed and propose possible strategies for combinatorial therapy of antioxidants to generate synergistic effect in FRDA patients.

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Section: Elamipretidementioning

confidence: 97%

Section: Elamipretidementioning

confidence: 99%

Emerging antioxidant therapies in Friedreich’s ataxia

Edzeamey,

Ramchunder,

Pourzand

et al. 2024

Front. Pharmacol.

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“…NOTE: This method was adapted from previous work done on permeabilized fibers by Pharaoh et al 11 . A high, un-inhibitory concentration of TMRM is used for quench mode, where the relationship of mMP and TMRM concentration in the matrix is inverted.…”

Section: High-resolution Fluorespirometry -Oxygen and Tmrm Fluorescen...mentioning

confidence: 99%

JoVE Video Dataset

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Peripheral mononuclear cells (PBMCs) exhibit robust changes in mitochondrial respiratory capacity in response to health and disease. While these changes do not always reflect what occurs in other tissues, such as skeletal muscle, these cells are an accessible and valuable source of viable mitochondria from human subjects. PBMCs are exposed to systemic signals that impact their bioenergetic state. Thus, expanding our tools to interrogate mitochondrial metabolism in this population will elucidate mechanisms related to disease progression. Functional assays of mitochondria are often limited to using respiratory outputs following maximal substrate, inhibitor, and uncoupler concentrations to determine the full range of respiratory capacity, which may not be achievable in vivo. The conversion of adenosine diphosphate (ADP) to adenosine triphosphate (ATP) by ATP-synthase results in a decrease in mitochondrial membrane potential (mMP) and an increase in oxygen consumption. To provide a more integrated analysis of mitochondrial dynamics, this article describes the use of high-resolution fluorespirometry to measure the simultaneous response of oxygen consumption and mitochondrial membrane potential (mMP) to physiologically relevant concentrations of ADP. This technique uses tetramethylrhodamine methylester (TMRM) to measure mMP polarization in response to ADP titrations following maximal hyperpolarization with complex I and II substrates. This technique can be used to quantify how changes in health status, such as aging and metabolic disease, affect the sensitivity of mitochondrial response to energy demand in PBMCs, T-cells, and monocytes from human subjects.

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Urolithin A induces cardioprotection and enhanced mitochondrial quality during natural aging and heart failure

Liu,

Faitg,

Tissot

et al. 2023

Preprint

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Cardiovascular diseases remain the primary cause of global mortality, necessitating effective strategies to alleviate their burden. Mitochondrial dysfunction is a driving force behind aging and chronic conditions, including heart disease. Here, we investigate the potential of Urolithin A (UA), a gut microbiome-derived postbiotic that enhances mitophagy, to ameliorate both age-related decline in cardiac function and cardiac failure. We highlight the significance of targeting mitochondria, by comparing gene expression changes in aging human hearts and cardiomyopathies. UA oral administration successfully counteracts mitochondrial and cardiac dysfunctions in preclinical models of aging and heart failure. UA improves both systolic and diastolic heart functions, distinguishing it from other mitochondrial interventions. In cardiomyocytes, UA recovers mitochondrial ultrastructural defects and decline in mitochondrial biomarkers occurring with aging and disease. These findings extend UA?s benefits to heart health, making UA a promising nutritional intervention to evaluate in the clinic to promote healthy cardiovascular function as we age.

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Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT)

Cited by 3 publications

References 39 publications

Emerging antioxidant therapies in Friedreich’s ataxia

Emerging antioxidant therapies in Friedreich’s ataxia

JoVE Video Dataset

Urolithin A induces cardioprotection and enhanced mitochondrial quality during natural aging and heart failure

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