Site-specific acetylation of adenine nucleotide translocase 1 at lysine 23 in human muscle

Finlayson, Jean; Barakati, Neusha; Langlais, Paul; Funk, Janet L.; Bustos, Rocio Zapata; Coletta, Dawn K.; Luo, Moulun; Willis, Wayne T.; Mandarino, Lawrence J.

doi:10.1016/j.ab.2021.114319

Cited by 4 publications

(7 citation statements)

References 18 publications

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“…A further study confirms that the acetylation of ANT1 at lysine23 increases the Km ADP of skeletal muscle 29 . The mechanism for the decreased affinity between acetylated ANT1 and ADP is demonstrated by Frinlayson group recently 30 . Lysine, a positively charged amino acid, contributes to a net positive charge of ANT1 which is critical for binding and transport of ADP/ATP with negative charges.…”

Section: Post‐translational Modification Of the Adenine Nucleotide Tr...supporting

confidence: 65%

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Adenine nucleotide translocase: Current knowledge in post‐translational modifications, regulations and pathological implications for human diseases

Chen

et al. 2023

The FASEB Journal

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Adenine nucleotide translocases (ANTs) are central to mitochondrial integrity and bioenergetic metabolism. This review aims to integrate the progresses and knowledge on ANTs over the last few years, contributing to a potential implication of ANTs for various diseases. Structures, functions, modifications, regulators and pathological implications of ANTs for human diseases are intensively demonstrated here. ANTs have four isoforms (ANT1-4), responsible for exchanging ATP/ADP, possibly composing of pro-apoptotic mPTP as a major component, and mediating FA-dependent uncoupling of proton efflux. ANT can be modified by methylation, nitrosylation and nitroalkylation, acetylation, glutathionylation, phosphorylation, carbonylation and hydroxynonenal-induced modifications. Compounds, including bongkrekic acid, atractyloside calcium, carbon monoxide, minocycline, 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid, cardiolipin, free long-chain fatty acids, agaric acid, long chain acyl-coenzyme A esters, all have an ability to regulate ANT activities. ANT impairment leads to bioenergetic failure and mitochondrial dysfunction, contributing to pathogenesis of diseases, such as diabetes (deficiency), heart disease (deficiency), Parkinson's disease (reduction), Sengers Syndrome (decrease), cancer (isoform shifting), Alzheimer's Disease (coaggregation with Tau), Progressive External Opthalmoplegia (mutation), and Fascioscapulohumeral muscular dystrophy (overexpression). This review improves the understanding of the mechanism of ANT in pathogenesis of human diseases, and opens a window for novel therapeutic strategies targeted on ANT in diseases.

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Section: Post‐translational Modification Of the Adenine Nucleotide Tr...supporting

confidence: 65%

“…Additionally, lysine23 is uniquely localized in the binding pocket where the electrostatic potential is highest. Thus, the acetylation of ANT1 at lysine23 plays a crucial role in regulating the ANT1 activity as an adenine nucleotide transporter 30 …”

Section: Post‐translational Modification Of the Adenine Nucleotide Tr...mentioning

confidence: 99%

Adenine nucleotide translocase: Current knowledge in post‐translational modifications, regulations and pathological implications for human diseases

Chen

et al. 2023

The FASEB Journal

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“…K22 is also an important positive residue within the pocket of AAC and its physiological significance has been confirmed by mutagenesis [ 21 ] and acetylation experiments [ 24 , 25 ]. However, K22 does not become involved in forming salt bridges with other residues in wild-type apo AAC [ 4 ], and therefore we did not investigate the impact of K22 in the current work.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations

Yao

et al. 2022

Molecules

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The mitochondrial ADP/ATP carrier (AAC) exports ATP and imports ADP through alternating between cytosol-open (c-) and matrix-open (m-) states. The salt bridge networks near the matrix side (m-gate) and cytosol side (c-gate) are thought to be crucial for state transitions, yet our knowledge on these networks is still limited. In the current work, we focus on more conserved m-gate network in the c-state AAC. All-atom molecular dynamics (MD) simulations on a variety of mutants and the CATR-AAC complex have revealed that: (1) without involvement of other positive residues, the charged residues from the three Px[DE]xx[KR] motifs only are prone to form symmetrical inter-helical network; (2) R235 plays a determinant role for the asymmetry in m-gate network of AAC; (3) R235 significantly strengthens the interactions between H3 and H5; (4) R79 exhibits more significant impact on m-gate than R279; (5) CATR promotes symmetry in m-gate mainly through separating R234 from D231 and fixing R79; (6) vulnerability of the H2-H3 interface near matrix side could be functionally important. Our results provide new insights into the highly conserved yet variable m-gate network in the big mitochondrial carrier family.

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“…Although metabolic flexibility during mild exercise appears to be independent of insulin sensitivity or aerobic capacity, there still was substantial variability among individuals in their capacity to shift the mix of carbohydrate and lipid oxidized. To examine this on a more mechanistic level, we used a novel mass spectrometric method 36 to quantify ANT1 acetylation and abundance in muscle biopsies. Factors that raise the apparent Km ADP for oxidative phosphorylation will raise the [ADP] needed to meet energy demands in resting or moderately exercising skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

“…ANT1 is the sole identifiable ANT isoform in human skeletal muscle 26 . ANT1 acetylation (%) and abundance were estimated using 13 C and 15 N-labeled synthetic peptides surrounding the acetylation site (lysine 23) as internal standards 36 . These synthetic heavy-labeled peptides had the same amino acid sequences as the tryptic peptides surrounding Lys23 that are observed in mass spectrometry experiments 27 .…”

Section: Methodsmentioning

confidence: 99%

Acetylation of Adenine Nucleotide Translocase, Fuel Selection, and Metabolic Flexibility in Human Skeletal Muscle

Barakati

Bustos

Coletta

et al. 2022

Preprint

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IntroductionHealthy, resting skeletal muscle primarily oxidizes lipid, but insulin resistant muscle oxidizes carbohydrate and shows metabolic inflexibility during hyperinsulinemia. It is unclear whether fuel selection and metabolic flexibility are dependent on insulin sensitivity in skeletal muscle performing mild exercise.Research Design and MethodsSedentary volunteers underwent a cycle exercise protocol using stepwise increments in power output (15, 30, and 45 watts) and indirect calorimetry to estimate fuel oxidation in working muscle. Euglycemic clamps, indirect calorimetry and muscle biopsies were used to measure insulin sensitivity and acetylation and content of Adenine Nucleotide Translocase 1 (ANT1), which might be involved in fuel selection via acetylation of lysine 23, which was quantified using mass spectrometry.ResultsMild exercise produced predicted rates of oxygen consumption (11-12 ml O2/min), with low and stable blood lactate, allowing use of indirect calorimetry to calculate a respiratory exchange ratio in working muscle (RERm). ANT1 acetylation varied from 0.6 to 21% (10.3 ± 1.2%). Exercising muscle mainly oxidized carbohydrate (45 ± 9, 62 ± 6, and 70 ± 5% of total at 15, 30, and 45watts). Multiple linear regression showed that RERm rose with increasing power output (P < 0.001) and was lower with greater protein content of ANT1 (P < 0.001). Insulin-stimulated glucose disposal, ANT acetylation, and VO2peak were not predictors of RERm.ConclusionsMildly exercising muscle in sedentary people prefers to oxidize carbohydrate independent of insulin sensitivity but depending on ANT1 protein content. The ability to oxidize lipid may be regulated by higher ANT1 content due to either higher mitochondrial abundance or greater ANT content per mitochondrial mass.

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Site-specific acetylation of adenine nucleotide translocase 1 at lysine 23 in human muscle

Cited by 4 publications

References 18 publications

Adenine nucleotide translocase: Current knowledge in post‐translational modifications, regulations and pathological implications for human diseases

Adenine nucleotide translocase: Current knowledge in post‐translational modifications, regulations and pathological implications for human diseases

Investigating the Broad Matrix-Gate Network in the Mitochondrial ADP/ATP Carrier through Molecular Dynamics Simulations

Acetylation of Adenine Nucleotide Translocase, Fuel Selection, and Metabolic Flexibility in Human Skeletal Muscle

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