The Mitochondrially Targeted Peptide Elamipretide (SS-31) Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake Through the Adenine Nucleotide Translocator (ANT)

Overview

Journal Geroscience

Specialty Geriatrics

Date 2023 Jul 18

PMID 37462785

Authors

Gavin Pharaoh

Varun Kamat

Sricharan Kannan

Rudolph S Stuppard

Jeremy Whitson

Miguel Martin-Perez

Wei-Jun Qian

Michael J MacCoss

Judit Villen

Peter Rabinovitch

Matthew D Campbell

Ian R Sweet

David J Marcinek

Affiliations

Soon will be listed here.

Abstract

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH (flavin adenine dinucleotide), O (oxygen), ELAM (elamipretide), -SH (free thiol), -SSG (glutathionylated protein).

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