Mitochondrial dysfunction in sepsis: nutritional strategies for restoring bioenergetic homeostasis

Why clinicians should know about it

• Picked for Nephrology (top studies of the week, 13 September 2026): Sepsis mitochondrial dysfunction, nutritional review
• Picked for Microbiology (medical) (top studies of the week, 13 September 2026): Mitochondrial dysfunction in sepsis, not microbiology
• Picked for Biochemistry (medical) (paper of the day, 11 September 2026): Mitochondrial dysfunction in sepsis, nutritional metabolic strategies

Abstract

BACKGROUND: Sepsis is increasingly recognized as a syndrome of maladaptive bioenergetic failure in which mitochondrial dysfunction-rather than being a secondary epiphenomenon-acts as a central driver of immune paralysis, endothelial incoherence, and multiple organ injury. Three interconnected molecular lesions are particularly consequential: impairment of the pyruvate dehydrogenase complex (PDC), excessive mitochondrial reactive oxygen species (mtROS) generation, and defective mitophagy. These mechanisms disrupt substrate oxidation, amplify oxidative injury, and prevent effective organelle turnover, creating a self-reinforcing bioenergetic collapse that persists despite hemodynamic stabilization. Nutritional molecules that target these specific mitochondrial nodes may offer a rational adjunctive strategy, yet their mechanistic basis and translational evidence have not been systematically integrated. METHODS: This mechanism‑driven review followed a PRISMA‑structured protocol to identify studies elucidating PDC impairment, mtROS excess, and mitophagy dysfunction in sepsis, as well as the therapeutic rationale for thiamine, carnitine, and coenzyme Q10 (CoQ10). We searched PubMed, Scopus, Web of Science, Cochrane Library, and ClinicalTrials.gov for English‑language literature published between January 1, 2005 and February 1, 2026. Eligible studies addressed mitochondrial dysfunction in sepsis, reported on at least one direct mitochondrial parameter (PDC activity, mtROS, mitophagy markers, membrane potential, or ATP), and evaluated the specified nutritional interventions. Of 1,324 initially identified records, 105 studies met inclusion criteria and were qualitatively synthesized. RESULTS: Preclinical evidence establishes that PDC impairment-driven by thiamine pyrophosphate deficiency-reduces pyruvate oxidation and increases lactate diversion, while excessive mtROS activates the NLRP3 inflammasome and amplifies inflammation, and defective mitophagy allows damaged organelles to accumulate, sustaining bioenergetic failure. These lesions propagate across immune, endothelial, parenchymal, and cerebral compartments, manifesting as immune paralysis, microcirculatory dysfunction, cardiac and renal impairment, and sepsis‑associated encephalopathy. Thiamine supplementation restores PDC activity and improves lactate clearance; L‑carnitine facilitates mitochondrial fatty acid trafficking, with post‑hoc analyses suggesting mortality benefit in patients with baseline acetylcarnitine >35 µM; and CoQ10 stabilizes electron transport, with trials reporting reduced vasopressor duration and improved SOFA scores. However, human data remain limited to small trials and subgroup analyses, and no large‑scale randomized controlled trial has definitively established mortality benefit for any of these agents. CONCLUSION: Mitochondrial dysfunction-specifically PDC impairment, mtROS excess, and mitophagy failure-is a core mechanistic axis of sepsis that drives bioenergetic collapse across multiple organ systems. Thiamine, carnitine, and CoQ10 target complementary nodes within this integrated damage network and are mechanistically grounded interventions, but the field is constrained by biological heterogeneity, lack of routine biomarkers, and inconsistent clinical translation. Future progress will require biomarker‑stratified trials that match intervention to dominant mitochondrial lesion, incorporate direct mitochondrial function endpoints, and test these nutrients within defined septic phenotypes, rather than as undifferentiated supplements.Overall, I believe that the inclusion of one or two well-designed original figures would significantly strengthen the manuscript and make it more engaging and accessible to readers.

Abstract as published, via PubMed.