Abstract

Mitochondrial diseases show unprecedented variability in different organ manifestations and ages of onset, but the mechanisms underlying such spectrum are poorly understood. Here, we report molecular mechanisms of how exogenous, actionable factors, or secondary metabolic pathway imbalance, have major effects on the disease course, both for disease onset and type of manifestation. For example, a specific recessively inherited mitochondrial disease allele in DNA polymerase gamma causes sensitivity to viral infections, allowing viral replication in early infection and causing a strong delayed proinflammatory response with dramatic effects on GABA -ergic neurons and liver homeostasis. Also, a muscle manifesting mitochondrial disease causes systemic NAD + deficiency – bodily B3 vitamin deficiency -the rescue of which has functional benefits. Targeting exogenous triggering factors or endogenous secondary metabolic consequences, based on mechanistic precision targets, are intriguing intervention strategies, with potential to delay disease-onset or restore functions.