Mitochondrial Dysfunction Linked to NAD+ Decline and DNA Repair Dysfunction: Preclinical Findings

Synopsis

Mitochondrial problems are common in aging and neurodegenerative diseases. In xeroderma pigmentosum group A (XPA), a disease caused by faulty DNA repair that leads to severe neurodegeneration, researchers found mitochondrial dysfunction both in computer models and living cells. XPA-deficient cells have damaged mitophagy (the process that clears faulty mitochondria), showing too much breakdown of a protein called PINK1 and increased mitochondrial membrane potential. This happens because the NAD+-SIRT1-PGC-1α pathway, important for mitochondrial health, is less active due to overactive DNA damage sensor PARP-1. Blocking PARP-1 or adding NAD+ precursors fixes these mitochondrial issues and improves lifespan in a worm model of XPA. Similar problems occur in other DNA repair disorders with neurodegeneration but not in one without it. This study highlights how communication between the cell nucleus and mitochondria is vital for keeping mitochondria healthy.

Journal

Cell