AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress

Perrino, Cinzia; Feliciello, Antonio; Schiattarella, Gabriele Giacomo; Esposito, Giovanni; Guerriero, Rosalia; Zaccaro, Laura; Gatto, Annarita Del; Saviano, Michele; Garbi, Corrado; Carangi, Rosa; Lorenzo, Emilio Di; Donato, Giuseppe; Indolfi, Ciro; Avvedimento, Vittorio Enrico; Chiariello, Massimo

doi:10.1093/cvr/cvq155

Cited by 61 publications

(108 citation statements)

References 23 publications

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“…Kim et al (8) found that through the PKA-dependent inhibitory phosphorylation of dynamin-related protein 1 (DRP1) and the PKA-independent control of fission protein 1 homolog (FIS1) complex formation with DRP1, AKAP121 is able to successfully control these mitochondrial fission events (8). (2,9,13). Through a PKA-independent pathway, AKAP121 is able to successfully mitigate the interaction between dynamin-related protein 1 (DRP1) and fission protein 1 homolog (FIS1), which would otherwise lead to FIS1/DRP1-induced fission events (8).…”

Section: Mitochondrial Fission-induced Apoptosis Begins With Akap121mentioning

confidence: 99%

“…During hypoxic conditions, SIAH2 binds AKAP121, causing the SIAH2/AKAP121 complex to enter the ubiquitin/proteasome pathway. Its degradation through this pathway leads to significantly decreased mitochondrial activity and ultimately cell death (2,13). availability of AKAP121 to control FIS1/DRP1-mediated fission resulted in inhibited oxidative phosphorylation, ultimately leading to cellular damage and cell death.…”

Section: Mitochondrial Fission-induced Apoptosis Begins With Akap121mentioning

confidence: 99%

“…Excessive damage to these membranes or any one of the mitochondria's key signaling pathways may result in significant loss of function in regards to oxidative phosphorylation, excessive reactive oxygen species (ROS) production, and the damage or loss of mDNA (13).…”

Section: Mitochondrial Dysfunction Is Averted By Akap121mentioning

confidence: 99%

“…MITOCHONDRIA ARE CRITICAL to cell function and survival, as they are vital in the maintenance and regulation of cellular homeostasis (4,13). One of the key regulatory molecules responsible for the control of this organelle is the A kinase anchor protein 121 (AKAP121) (2).…”

mentioning

confidence: 99%

“…One of the key regulatory molecules responsible for the control of this organelle is the A kinase anchor protein 121 (AKAP121) (2). Acting as a scaffold protein, AKAP121 functions to anchor protein kinase A (PKA) and other signaling molecules onto the outer mitochondrial membrane (13). By performing this function, AKAP121 allows for the phosphorylation of specific key substrate molecules in the vicinity of the mitochondrial membrane, and it therefore achieves effective spatial and temporal control over their phosphorylation state (13).…”

mentioning

confidence: 99%

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Pivotal role of AKAP121 in mitochondrial physiology

Czachor

Failla

Lockey

et al. 2016

American Journal of Physiology-Cell Physiology

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In this Perspective, we discuss some recent developments in the study of the mitochondrial scaffolding protein AKAP121 (also known as AKAP1, or AKAP149 as the human homolog), with an emphasis on its role in mitochondrial physiology. AKAP121 has been identified to function as a key regulatory molecule in several mitochondrial events including oxidative phosphorylation, the control of membrane potential, fission-induced apoptosis, maintenance of mitochondrial Ca2+ homeostasis, and the phosphorylation of various mitochondrial respiratory chain substrate molecules. Furthermore, we discuss the role of hypoxia in prompting cellular stress and damage, which has been demonstrated to mediate the proteosomal degradation of AKAP121, leading to an increase in reactive oxgyen species production, mitochondrial dysfunction, and ultimately cell death.

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Section: Mitochondrial Fission-induced Apoptosis Begins With Akap121mentioning

confidence: 99%

Section: Mitochondrial Fission-induced Apoptosis Begins With Akap121mentioning

confidence: 99%

Section: Mitochondrial Dysfunction Is Averted By Akap121mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pivotal role of AKAP121 in mitochondrial physiology

Czachor

Failla

Lockey

et al. 2016

American Journal of Physiology-Cell Physiology

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AKAP1 Deficiency Attenuates Diet‐Induced Obesity and Insulin Resistance by Promoting Fatty Acid Oxidation and Thermogenesis in Brown Adipocytes

Zhao

et al. 2021

Advanced Science

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Altering the balance between energy intake and expenditure is a major strategy for treating obesity. Nonetheless, despite the progression in antiobesity drugs on appetite suppression, therapies aimed at increasing energy expenditure are limited. Here, knockout ofAKAP1, a signaling hub on outer mitochondrial membrane, renders mice resistant to diet‐induced obesity.AKAP1 knockout significantly enhances energy expenditure and thermogenesis in brown adipose tissues (BATs) of obese mice. Restoring AKAP1 expression in BAT clearly reverses the beneficial antiobesity effect in AKAP1−/− mice. Mechanistically, AKAP1 remarkably decreases fatty acid β‐oxidation (FAO) by phosphorylating ACSL1 to inhibit its activity in a protein‐kinase‐A‐dependent manner and thus inhibits thermogenesis in brown adipocytes. Importantly, AKAP1 peptide inhibitor effectively alleviates diet‐induced obesity and insulin resistance. Altogether, the findings demonstrate that AKAP1 functions as a brake of FAO to promote diet‐induced obesity, which may be used as a potential therapeutic target for obesity.

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Phosphorylation, compartmentalization, and cardiac function

Collins

Scott

2022

IUBMB Life

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Protein phosphorylation is a fundamental element of cell signaling. First discovered as a biochemical switch in glycogen metabolism, we now know that this posttranslational modification permeates all aspects of cellular behavior. In humans, over 540 protein kinases attach phosphate to acceptor amino acids, whereas around 160 phosphoprotein phosphatases remove phosphate to terminate signaling. Aberrant phosphorylation underlies disease, and kinase inhibitor drugs are increasingly used clinically as targeted therapies. Specificity in protein phosphorylation is achieved in part because kinases and phosphatases are spatially organized inside cells. A prototypic example is compartmentalization of the cyclic adenosine 3′,5′‐monophosphate (cAMP)‐dependent protein kinase A through association with A‐kinase anchoring proteins. This configuration creates autonomous signaling islands where the anchored kinase is constrained in proximity to activators, effectors, and selected substates. This article primarily focuses on A kinase anchoring protein (AKAP) signaling in the heart with an emphasis on anchoring proteins that spatiotemporally coordinate excitation‐contraction coupling and hypertrophic responses.

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AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress

Abstract: These data suggest that AKAP121 regulates the response to stress in cardiomyocytes, and therefore AKAP121 downregulation might represent an important event contributing to the development of cardiac dysfunction.

Cited by 61 publications

References 23 publications

Pivotal role of AKAP121 in mitochondrial physiology

Pivotal role of AKAP121 in mitochondrial physiology

AKAP1 Deficiency Attenuates Diet‐Induced Obesity and Insulin Resistance by Promoting Fatty Acid Oxidation and Thermogenesis in Brown Adipocytes

Phosphorylation, compartmentalization, and cardiac function

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