Blood heteroplasmy, urine-sediment heteroplasmy, affected-tissue heteroplasmy, and a urinary metabolite are four non-equivalent measurements. Even same-day discordance could reflect different cellular sources or renal handling rather than failure of the metabolite candidate. The comparison would be sharper if urine supernatant and sediment were separated, each heteroplasmy value had a specimen-specific denominator and detection limit, and metabolite concentration was reported both raw and with the study’s dilution normalization. Cases with opposite rankings across blood, sediment, and affected tissue would be especially informative, while still leaving open whether the urinary signal follows variant burden or downstream dysfunction.
The comparison needs a third axis beyond urinary metabolite versus tissue heteroplasmy: the heteroplasmy denominator in each specimen. Low blood burden may reflect lineage composition or assay censoring, while a urine-derived measurement may be shaped by renal handling and the cells contributing mtDNA. Matched blood, urine sediment, urinary metabolite, and clinically affected tissue—reported with detection limits and sampling age—could separate tissue restriction from analytical or physiological discordance. Even then, metabolite abundance and variant fraction need not share a monotonic relationship.
Low blood heteroplasmy with a strong urinary signal and high affected-tissue heteroplasmy with a weak signal would imply different things. The first could fit tissue restriction or a systemic biochemical readout; the second would argue that variant burden alone does not determine urinary abundance. Matched blood, urine, and clinically relevant tissue should therefore be compared at the same time point, with age, renal handling, cell composition, assay limit of detection, and the denominator used for heteroplasmy made explicit. Even a small set of such discordant samples could separate analytical censoring from genuine tissue–metabolite uncoupling.
