The consequences of mitochondrial dysfunction and upregulated glycolysis on innate and adaptive immune responses
The finding
This 2026 review by Fabrizio Marcucci and Cristiano Rumio synthesizes how mitochondrial dysfunction and compensatory fermentative glycolysis (the Warburg shift) operate as a dual-edged regulatory axis in immunity. When oxidative phosphorylation (OXPHOS) collapses, the cell upregulates fermentative glycolysis as an emergency "necrosis defense" to maintain basic ATP levels and prevent catastrophic membrane rupture with uncontrolled DAMP release. Simultaneously, the review maps how non-canonical "moonlighting" functions of glycolytic enzymes and overflow metabolites orchestrate contradictory immune fates: pro-inflammatory amplification via PKM2–HIF-1α transcription of IL-1β and NLRP3/AIM2 assembly, juxtaposed against profound epigenetic and post-translational immunosuppression mediated by histone lactylation (e.g., H3K18la) and pyruvate-driven STAT1 Lys201 pyruvilation.
Where it fits
This synthesis sits squarely across the interface between Loop B (Mitochondrial / NLRP3 Inflammasome) and Loop A (Type I Interferon / JAK-STAT) in the SAMHD1 p.A565T architecture:
- The Emergency Necrosis Defense (Loop B): In the SAMHD1 framework, mitochondrial nucleotide overload (PNC1/2) and POLG stalling collapse membrane potential (ΔΨm). Marcucci & Rumio explain why this does not immediately trigger fulminant cell lysis: compensatory aerobic glycolysis generates just enough ATP to hold off bioenergetic necrosis (inhibiting MLKL-driven rupture). However, the trade-off is massive intracellular accumulation of pyruvate and lactic acid.
- Selective Antiviral Uncoupling via STAT1 Pyruvilation: The authors highlight the emerging discovery (Zuo et al., Cell 2026) that glycolytic pyruvate overflow covalently modifies STAT1 at Lys201. This sterically blocks STAT1–STAT2 heterodimerization (ISGF3), selectively turning down antiviral ISG transcription while leaving NF-κB, STAT3, and IFN-γ/GAF signaling fully intact. This directly resolves a core paradox in the A565T phenotype: heightened viral vulnerability coexisting with unremitting autoinflammatory drive.
- The Epigenetic Lactylation Lock & Multi-Day PEM: Excess lactate drives H3K18la histone modifications and synovial T-cell entrapment. While initially protective against runaway inflammation, persistent lactylation locks macrophages into a refractory, exhausted state—providing a compelling mechanistic basis for prolonged post-exertional malaise (PEM) and refractory fatigue.
Caveats
- Review Synthesis, Not Primary Genetics: The paper aggregates findings across oncology, toxicology (e.g., metformin, tigecycline), and infection models; it does not measure primary cells with heterozygous SAMHD1 mutations.
- Dose & Microenvironment Dependency: As the authors emphasize, the immunomodulatory polarity of lactate (inflammatory vs. immunosuppressive) is highly sensitive to local extracellular pH, cell-type transporter expression (MCTs), and acute vs. chronic duration.
- Stoichiometry of PTMs: The physiological abundance of Lys201 pyruvilation relative to standard phosphorylation (p-Y701) in non-transformed human immune cells remains to be quantitatively benchmarked via targeted mass spectrometry.
What to watch
The key translational question is whether pharmacological modulation of mitochondrial substrate influx (e.g., inner-membrane PNC1/2 carriers) or lactic acid dynamics can release the refractory H3K18la chromatin lock and normalize antiviral ISGF3 assembly without compromising the glycolytic energy buffer that protects cells from necrotic collapse.
Source: The consequences of mitochondrial dysfunction and upregulated glycolysis on innate and adaptive immune responses — Cell Signaling, Inflammation & Disease 2026.