1 (NRF1). The NRFs, in turn, activate the mitochondrial transcription factor A (tfam), which is directly responsible for transcribing nuclear-encoded mitochondrial proteins. This includes both structural mitochondrial proteins as well as those involved in mtDNA transcription, translation, and repair. PGC- 1β, a protein that is structurally similar to PGC-1α, is also involved in regulating mitochondrial biogenesis, but differs in that it does not get increased in response to exercise. While there have been significant increases in mitochondria found in tissues where PGC-1α is overexpressed, as the cofactor interacts with these key transcription factors, knockout mice with disrupted PGC-1α are still viable and show normal mitochondrial abundance. Thus, PGC-1α is not required for normal development of mitochondria in mice, but when put under physiological stress, these mice exhibit diminished tolerance compared to mice with normal levels of PGC-1α. Similarly, in knockout mice with disrupted PGC-1β, the mice showed mostly normal levels of mitochondrial function with decreased ability to adapt to physiological stress. However, a double knockout experiment of PGC-1α/β created mice that died mostly within 24 hours by defects in mitochondrial maturation of cardiac tissue. These findings suggest that while both PGC-1α and PGC- 1β do not each solely establish a cell’s ability to perform mitochondrial biogenesis, together they are able to complement each other for optimal mitochondrial maturation and function during periods of physiological stress. AMP-activated kinase (AMPK) also regulates mitochondrial biogenesis by phosphorylating and activating PGC-1α upon sensing an energy deficiency in muscle. In mice with reduced ATP/AMP ratios that would occur during exercise, the energy depletion has been shown to correlate with AMPK activation. AMPK activation then continued to activate PGC- 1α and NRFs in these mice, and mitochondrial biogenesis was stimulated. Aging The capacity for mitochondrial biogenesis has been shown to decrease with age, and such decreased mitochondrial function has been associated with diabetes and cardiovascular disease. Aging and disease can induce changes in the expression levels of proteins involved in the fission and fusion mechanisms of mitochondria, thus creating dysfunctional mitochondria. One hypothesis for the detrimental results of aging is associated with the loss of telomeres, the end segments of chromosomes that protect genetic information from degradation. Telomere loss has also been associated with decreased mitochondrial function. Deficiency of telomerase reverse transcriptase (TERT), an enzyme that plays a role in preserving telomeres, has been correlated with activated p53, a protein that suppresses PGC-1α. Therefore, the loss