Metabolic reprogramming during hyperammonemia targets mitochondrial function and postmitotic senescence

Kumar, Avinash; Welch, Nicole; Mishra, Saurabh; Bellar, Annette; Silva, Rafaella Nasciemento; Li, Ling; Singh, Sanjai; Sharkoff, Mary; Kerr, Alexis; Chelluboyina, Aruna; Sekar, Jinendiran; Attaway, Amy; Hoppel, Charles L.; Willard, Belinda; Davuluri, Gangarao; Dasarathy, Srinivasan

doi:10.1172/jci.insight.154089

Cited by 18 publications

(60 citation statements)

References 50 publications

(106 reference statements)

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“…Synapse and synaptosome are regulated by PKA ( Hoover et al., 2001 ; Munno et al., 2003 ), a pathway consistently enriched during both 6hAmAc and 24hAmAc. A number of other regulatory responses that were identified are consistent with previous reports of RNAseq and proteomics responses and pathway enrichments during skeletal muscle hyperammonemia reported previously ( Kumar et al., 2021 ; Welch et al., 2021 ).…”

Section: Resultssupporting

confidence: 90%

“…However, of the 19 shared DEP and DEpP, the expression patterns of 10 molecules were concordant whereas the remaining had a discordant pattern ( Figure S2 B). Functional enrichment analysis of all overlapping DEpP/DEP showed enrichment of apoptosis-induced DNA fragmentation and formation of senescence-associated heterochromatin foci that are consistent with reports that ammonia promotes senescence in multiple cell types ( Gorg et al., 2015 ; Jo et al., 2021 ; Kumar et al., 2021 ).…”

Section: Resultssupporting

confidence: 88%

“…Dysregulated ammonia metabolism occurs in a number of chronic diseases, including liver cirrhosis, heart failure, and chronic obstructive pulmonary disease ( Dasarathy and Hatzoglou, 2018 ; Medeiros et al., 2014 ; Valero et al., 1974 ). During the consequent hyperammonemia, skeletal muscle becomes a major organ for ammonia uptake ( Ganda and Ruderman, 1976 ; Lockwood et al., 1979 ; Qiu et al., 2013 ) with complex molecular and metabolic perturbations( Dasarathy and Hatzoglou, 2018 ; Davuluri et al., 2016a , 2016b ; Kumar et al., 2021 ; Medeiros et al., 2014 ; Valero et al., 1974 ; Welch et al., 2021 ). However, circulating and skeletal muscle ammonia concentrations do not parallel each other, which may be because of an increased expression of inducible skeletal muscle ammonia transporter, RhBG ( Kant et al., 2019 ; McDaniel et al., 2016 ; Qiu et al., 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Shared and unique phosphoproteomics responses in skeletal muscle from exercise models and in hyperammonemic myotubes

et al. 2022

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Shared and unique phosphoproteomics responses in skeletal muscle from exercise models and in hyperammonemic myotubes

et al. 2022

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“…Hyperammonemia has been shown to result in oxidative stress in central nervous system of HE, as well as mitochondrial dysfunction 13,36,37 . Oxidative stress has been looked for to aggravate the cerebral effects of ammonia in patients with liver disease 38 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial redox stress based treatment of hepatic encephalopathy

Bai

et al. 2022

Preprint

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Increased GABAergic tone in the substantia nigra reticulum (SNr) causes bradykinesia in hepatic encephalopathy (HE), but its mechanisms need to be further elucidated. In the present study, FosCreERT2 (TRAP2) strategy and designer receptors exclusively activated by designer drugs (DREADDs) strategy revealed that MHE and ammonia activated SNr Gad2-expressing GABA population and mitochondria in such population were sensitive to ammonia imbalance. We have shown that the chemogenetic inhibition of this population, or targeted overexpression of mitochondrial Ucp2 in such population, or systemic application of a mitochondrial-targeting antioxidant drug MitoQ, could ameliorate HE effectively, by relieving neuronal oxidative stress and improving mitochondrial dysfunction. Our results identify activation of Gad2 neurons and oxidative stress-induced mitochondrial abnormalities in SNr as critical determinants in HE and demonstrate the potential for targeting this pathway in HE.

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“…The development of high-resolution proteomic screening has led to advances in the development of biomarkers based on metabolomic profiling [ 15 ] and the detection of temporal events, which can be implicated in the development of MD [ 16 ]. All of these developments have led to the synthesis of information derived from multi-omic studies [ 17 , 18 , 19 ] with the objective of arriving at a definitive and comprehensive overview of the regulatory factors involved in the development of MDs.…”

Section: Introductionmentioning

confidence: 99%

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

Rodrigues

Yong

Bhuiyan

et al. 2022

Biology

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Advances in data acquisition via high resolution genomic, transcriptomic, proteomic and metabolomic platforms have driven the discovery of the underlying factors associated with metabolic disorders (MD) and led to interventions that target the underlying genetic causes as well as lifestyle changes and dietary regulation. The review focuses on fourteen of the most widely studied inherited MD, which are familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, Maple syrup urine disease, Metachromatic leukodystrophy, Mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS), Niemann-Pick disease, Phenylketonuria (PKU), Porphyria, Tay-Sachs disease, Wilson’s disease, Familial hypertriglyceridemia (F-HTG) and Galactosemia based on genome wide association studies, epigenetic factors, transcript regulation, post-translational genetic modifications and biomarker discovery through metabolomic studies. We will delve into the current approaches being undertaken to analyze metadata using bioinformatic approaches and the emerging interventions using genome editing platforms as applied to animal models.

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Metabolic reprogramming during hyperammonemia targets mitochondrial function and postmitotic senescence

Cited by 18 publications

References 50 publications

Shared and unique phosphoproteomics responses in skeletal muscle from exercise models and in hyperammonemic myotubes

Shared and unique phosphoproteomics responses in skeletal muscle from exercise models and in hyperammonemic myotubes

Mitochondrial redox stress based treatment of hepatic encephalopathy

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

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