Year 1

Great progress has been made in determining how mitochondria function in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) in comparison to differentiated derivative cells, such as fibroblasts, and cancer cells. It has been assumed without much data, based largely on overall appearance under the microscope, that human pluripotent stem cells (hPSCs) contain underdeveloped, bioenergetically inactive mitochondria. In contrast, differentiated cells harbor a mature mitochondrial network, with oxidative phosphorylation (OXPHOS) as the main energy source. A role for mitochondria in hPSC bioenergetics therefore remained uncertain. In just completed work funded by this CIRM Basic Biology I grant (RB1-01397), we have shown that hPSC mitochondria have functional respiration complexes that consume oxygen, which is inconsistent with the notion that hPSC mitochondria are non-functional. Despite this, energy generated in hPSCs is mainly by mechanisms that are independent of mitochondria. To help maintain intact hPSC mitochondria and overall cell viability, energy from imported glucose is burned rather than produced within mitochondria, forming an overall unusual pattern of energy utilization in hPSCs compared with differentiated cells. Combined, our data show that hPSC mitochondria are energetically functional and suggest a key mechanism(s) remaining to be discovered that converts this unique form of hPSC bioenergetics to oxygen consumption-coupled energy production within mitochondria during differentiation. Results of this work are currently under submission for publication.