Age-related decrease in mitochondrial lncMtDloop expression potentiates Alzheimer's pathogenesis

Abstract

Loss of mitochondrial homeostasis are evident in Alzheimer's disease (AD)1. However, the underlying mechanisms remain largely elusive. In this study, we report that lncMtDloop, an age-related and conserved long noncoding RNA derived from mitochondrial DNA (mtDNA) D-loop, is crucial for sustaining mitochondrial transcription and homeostasis, and associates with Alzheimer’s pathogenesis. Notably, the level of lncMtDloop expression is diminished in the brains of human AD patients and the 3xTg mouse model, whereas the failure to recruit mitochondrial transcription factor A (TFAM) leads to the deregulated mitochondrial transcription. Restoring lncMtDloop expression not only significantly improves mitochondrial transcription, morphology and function, but also enhances mitophagy, ameliorates AD-like pathology, which these subcellular effects extend to a dramatic reversal of deficits in synaptic and cognitive behaviors of the 3xTg mouse model. Collectively, our findings show the decreased lncMtDloop expression potentiates AD risk, thereby revealing an unexpected mitochondrial mechanism contributing to AD pathogenesis and opens a new door for therapeutic intervention.