Mitochondria in pluripotent stem cells: stemness regulators and disease targets

Abstract

Beyond their canonical role in efficient ATP production through oxidative metabolism, mitochondria are increasingly recognized as critical in defining stem cell function and fate. Implicating a fundamental interplay within the epigenetics of eukaryotic cell systems, the integrity of mitochondria is found vital across the developmental/differentiation spectrum from securing pluripotency maintenance to informing organotypic decisions. This overview will discuss recent progress on examining the plasticity of mitochondria in enabling the execution of programming and reprogramming regimens, as well as the application of nuclear reprogramming and somatic cell nuclear transfer as rescue techniques to generate genetically and functionally corrected pluripotent stem cells from patients with mitochondrial DNA-based disease.

Figure 1

Mitochondria contribute to stemness maintenance. By reducing their reliance on oxidative metabolism for ATP generation and potentially utilizing ATP to maintain mitochondria membrane potential, stem cells can repurpose their mitochondria to cataplerosis. These mitochondria-derived metabolites are utilized as precursors for the anabolic generation of cell building blocks and serve as substrates for reactions that add or remove epigenetic marks that are critical for directing cell fate.

Figure 2

Creating disease-free pluripotent stem cells from patients with mitochondrial DNAN (mtDNA)-based disease. Nuclear reprogramming segregates wildtype and mutant mt-DNA enabling the clonal expansion of mutation-free induced pluripotent stem cells (iPSC) from patients with heteroplasmic mt-DNA disease. Homoplasmic mtDNA disease requires a complete mitochondria replacement strategy using somatic cell nuclear transfer (SCNT) to generate mutation free nuclear transfer embryonic stem cells (NT-ESC).