FIGURE 1: Hypothetical model for preventing AD-associated mitochondrial dysfunction triggered by the accumulation of UBB⁺¹ and aberrant tau.

Hyperphosphorylated forms of the microtubule-associated protein tau interfere with mitochondrial function (1). In parallel, the cellular accumulation of UBB⁺¹ induces UPS dysfunction (2) thereby indirectly impairing mitochondria. The mitochondrion-associated UPS, which depends on VMS1, ensures the local protein quality at mitochondria (3) and by this way protects from neuronal cell loss elicited by damaged mitochondria.