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Stable Bioreactor Control Reveals Acidic pH–Driven Metabolic Reprogramming and Mitochondrial Dysfunction in Human Lymphoblastoid Cells

ABSTRACT: Human cells require pH regulation to maintain physiological function, yet the molecular consequences of acidic environments remain incompletely understood. Here, we employ a gas-only bioreactor to control pH, oxygen, and temperature. Integrated Omics analyses reveal that acidic pH induces a glycolytic metabolic shift, suppresses proliferation, and promotes accumulation of lactate and oncometabolites alongside mitochondrial dysfunction. Acidic conditions increase reactive oxygen species (ROS) and activate inflammatory and immune pathways, leading to heteroplasmic enrichment of a pathogenic mitochondrial mutation. Acidic pH depletes intracellular NAD⁺, partly driven by PARP1 activation. Restoring NAD⁺ through nicotinamide mononucleotide (NMN) supplementation partially rescues proliferation and stress-associated transcription, while elevating NAD+ levels by NMN or PARP1 inhibition reverses heteroplasmic enrichment of mutant mitochondrial DNA. These findings underscore the role of pH homeostasis in coordinating metabolism, redox balance, and immune signaling, and identify NAD⁺ metabolism as a mechanistic link between acidic microenvironments, mitochondrial genome instability, and immune–metabolic remodeling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254130 | GEO | 2026/03/11

REPOSITORIES: GEO

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Stable Bioreactor Control Reveals Acidic pH–Driven Metabolic Reprogramming and Mitochondrial Dysfunction in Human Lymphoblastoid Cells

Project description:Human cells require precise pH regulation to maintain optimal physiological functions, yet the molecular impacts of acidic environments remain underexplored due to the lack of technologies capable of precisely controlling the cell culture environment. Here, we employed a gas-only bioreactor to stably control pH, dissolved oxygen, and temperature during the culture of human B lymphoblastoid cells. Integrated transcriptomic, epigenomic, and metabolomic analysis revealed that acidic pH (6.8) induces a metabolic shift towards glycolysis, suppresses energy-intensive processes such as cell proliferation, and triggers intracellular accumulation of lactate and oncometabolites and mitochondrial dysfunction. This environment also elevates reactive oxygen species (ROS) and upregulates inflammatory and immune pathways, leading to heteroplasmic shifts in a pathogenic mitochondrial mutation. Mechanistically, acidic pH caused marked depletion of intracellular NAD⁺ driven in part by PARP1 activation, and restoration of NAD⁺ levels via nicotinamide mononucleotide supplementation or PARP1 inhibition partially rescued cellular proliferation, mitochondrial genomic integrity, and stress-associated transcriptional programs. These findings highlight the critical role of pH homeostasis in cellular metabolism and immune response, offering insights into the cellular adaptations to acidic stress, which may inform therapeutic strategies for conditions like cancer and metabolic disorders.

2026-03-11 | GSE317794 | GEO

Nicotinamide Mononucleotide Requires SIRT3 to Improve Cardiac Function and Bioenergetics in a Friedreich’s Ataxia Cardiomyopathy Model

Project description:Martin et al. JCI Insigh (2017). Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action is via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s Ataxia cardiomyopathy mouse model (FXNKO). At baseline, the FXNKO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXNKO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3KO and SIRT3KO/FXNKO (dKO) knockout models. The improvement in cardiac function upon NMN treatment in the FXNKO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio- protection, SIRT3 mediates NMN-induced improvements in both cardiac and extra-cardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich’s Ataxia patients.

2017-07-21 | PXD006754 | Pride

Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice

Project description:NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12 month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

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Nicotinamide mononucleotide, a key NAD+ precursor, treats the pathophysiology of diet- and age-induced diabetes

Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).

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Slc12a8 is a nicotinamide mononucleotide transporter that counteracts aging

Project description:NAD+ levels decline in multiple tissues over age, causing various age-associated pathophysiologies. Nicotinamide mononucleotide (NMN) is a key NAD+ intermediate that promotes NAD+biosynthesis and counteracts age-associated physiological decline. However, how NMN transport is regulated remains unknown. Here we report a novel NMN transporter encoded by the Slc12a8 gene. Slc12a8 is highly expressed and regulated by NAD+ in the small intestine. Knocking down this gene abrogates the transport of NMN in vitro and in vivo. Slc12a8 exhibits specificity to NMN and dependency on the sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, due to decreases in NMN uptake traced by doubly labeled isotopic NMN. Slc12a8 expression is upregulated in the aged ileum, contributing to the maintenance of NAD in aged mice. Thus, this newly identified NMN transporter plays a critical role in counteracting NAD+ decline during aging.

2019-01-01 | GSE118365 | GEO

Nicotinamide mononucleotide increases muscle insulin sensitivity in women with prediabetes

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2021-05-01 | GSE157988 | GEO

Hydrolyzing NAD to NMN and AMP by SelO is required for mitochondria homeostasis

Project description:<p>The regulation of mitochondrial nicotinamide adenine dinucleotide (mNAD) is crucial for numerous life processes. However, until now, no metabolic reaction responsible for downregulating mNAD has been identified. Through in silico screening of potential NAD-binding proteins, we discovered a previously unrecognized reaction where NAD+ (or NADH) is hydrolyzed to NMN (or NMNH) and AMP in mitochondria. This reaction is catalyzed by the selenoprotein SelO, with Mn2+ serving as an essential cofactor. Selenocysteine 667 on the SelO protein plays a critical role in its NAD-hydrolyzing activity. SelO directly interacts with the mitochondrial trifunctional complex, and inhibits lipid β-oxidation, where NAD+ is required as an essential cofactor. This reaction is enhanced by a gradual increase in pH, which signals heightened mitochondrial catabolism, and it downregulates matrix pH as a negative feedback mechanism to maintain mitochondrial homeostasis. The NAD-hydrolyzing activity of SelO and its role in lipid oxidation are conserved across distant species, from mammalian cells to bacteria. Furthermore, SelO has been identified as a direct target of scutellarein, a clinically used agent for various ailments. These findings reveal a conserved mechanism for spatiotemporal NAD regulation, and highlight its physiological significance across both prokaryotes and eukaryotes.</p>

2026-01-07 | MTBLS13624 | MetaboLights

Mitochondrial PARP1 Regulates NAD+-dependent Poly ADP-ribosylation on Mitochondrial Nucleoids

Project description:Poly ADP-ribose (PAR) polymerases (PARPs) play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and PARylation. The existence of mtPARP is controversial, and the biological roles for mtPARP induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induces PARylation which is suppressed by PARP inhibitor olaparib treatment. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA) labeling. To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) . We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and NAD+ dependent mtPARP1 activity contributes to mtDNA transcription regulation.

2022-08-20 | GSE182533 | GEO

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Project description:Sepsis remains a leading cause of mortality and long-term disability, with survivors frequently developing intensive care unit–acquired weakness (ICU-AW) as part of post–intensive care syndrome. Here, to identify a nutritional therapy for ICU-AW, we investigated the mechanisms underlying sepsis-induced skeletal muscle dysfunction using a cecal slurry-induced sepsis mouse model. Although body weight and skeletal muscle mass recovered at 14 days after sepsis induction, muscle strength remained impaired, accompanied by persistent mitochondrial abnormalities. Transcriptomic analysis revealed that the pathways termed “Sirtuin signaling pathway” and “Mitochondrial dysfunction” significantly enriched with downregulation of Sirt3 which is a major mitochondrial NAD⁺-dependent deacetylase. Biochemical analyses confirmed increased acetylated lysine of mitochondrial proteins in septic muscle tissue. Among them, mass spectrometry identified complex I subunits as candidate substrates of Sirt3. Knockdown of Sirt3 in C2C12 myotubes impaired mitochondrial respiration, whereas treatment with β-nicotinamide mononucleotide (β-NMN) partially rescued energy production. In vivo, acute-phase administration of β-NMN preserved mitochondrial morphology and restored muscle strength without altering muscle mass. These findings demonstrate that sepsis induces mitochondrial dysfunction and persistent muscle weakness through Sirt3 downregulation, and highlight β-NMN supplementation as a promising NAD⁺-targeted therapeutic strategy for mitigating ICU-AW.

2026-02-28 | GSE310375 | GEO

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