The mitochondrially targeted peptide elamipretide (SS-31) 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:10.1007/s11357-023-00861-y

Cited by 12 publications

(3 citation statements)

References 38 publications

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“…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: Antioxidantsmentioning

confidence: 99%

“…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: Antioxidantsmentioning

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: Antioxidantsmentioning

confidence: 99%

Section: Antioxidantsmentioning

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%

High-Resolution Fluorespirometry to Assess Dynamic Changes in Mitochondrial Membrane Potential in Human Immune Cells

Valencia,

Pharaoh,

Brandao

et al. 2024

JoVE

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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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