Mitochondrial dysfunction in PBMC: a potential sensor for metabolic dysfunction-associated steatotic liver disease and therapeutic insight for NAD+-increasing strategies

The epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly growing worldwide. Thus, there is an urgent need for novel, non-invasive, and reliable biomarkers to replace liver biopsy for the diagnosis and prognosis of MASLD. Circulating peripheral blood mononuclear cells (PBMCs) are highly responsive to various stimuli and physiological changes. Beyond their immunomodulatory role, PBMC may act as metabolic sensors in several cardiometabolic disorders, including MASLD, with their metabolic programs shifting accordingly. Recent evidence suggests a link between impaired mitochondrial bioenergetics in PBMC and MASLD. Additionally, impaired mitochondrial respiration is intricately linked to the intracellular depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) in various cell types. Accumulating preclinical and clinical data show that NAD+-increasing strategies may protect against MASLD by restoring intracellular NAD+ pools and improving mitochondrial performance. This review will focus on [i] the relevance of mitochondrial dysfunction, including impaired bioenergetics, in PBMC as a marker for the diagnosis and prognosis of MASLD, and [ii] the potential benefits of NAD+ precursors in MAFLD and their relationship with improved mitochondrial respiration in blood immune cells.