In cooperation with many nuclear-encoded proteins, mtDNA genes contain the instructions to components for essential cell processes, such as generating energy. Mitochondrial DNA copy number, a measure of the number of mitochondrial genomes per cell, is a minimally invasive proxy for mitochondrial function and has been associated with several aging-related diseases and all-cause mortality. However, we still only know a little about how metabolism inside mitochondria affects mtDNA maintenance and replication, let alone how these processes may underlie aging and longevity.
To address this problem, Kang and colleagues created a new method for measuring metabolism within mitochondria to understand how mitochondrial metabolism regulates mtDNA replication. With this method, which they called SLO, The Japanese research team genetically manipulated levels of an enzyme called ‘twinkle’ — a component of mtDNA replication machinery that can increase the number of mitochondria.
By increasing mtDNA copy number through twinkle manipulation, Kang and colleagues found that several components related to metabolism changed, including increases in nucleotides and NAD+ — a vital molecule that serves as an essential factor for innumerable cell processes, including mitochondrial energy generation. Kang and colleagues speculate that these results suggest that nucleotide and NAD+ increases may result from increased demand for components required for mtDNA replication.