Several lines of evidence support an association of mitochondrial DNA (mtDNA) mutations for the pathogenesis of Alzheimer’s disease (AD). Mitochondrial dysfunction and evidence of oxidative stress have been described as pathological features of AD. However, a direct causative linkage between specific mtDNA mutation and AD etiology is still missing. Therefore, we established new AD mouse models with naturally occurring mtDNA mutations and assessed their functional relevance for beta-amyloid (Abeta) proteostasis. We show that an altered mitochondrial energy metabolism resulting in enhanced ATP production, promotes microglial Abeta degradation as well as Abeta export rates. Thus, we provide for the first time direct in vivo evidence for a contribution of specific mtDNA mutations in decreasing age-dependent Abeta deposition.