UC San Diego
Mitochondrial Quality Control is Essential for Cardiac Progenitor Cell and Cardiac Function
- Author(s): Orogo, Amabel
- Advisor(s): Gustafsson, Åsa
- et al.
Cardiac progenitor cells (CPCs) have the potential to repair the myocardium after pathological injury. Mitochondria regulate stem cell function and adapt to the metabolic needs of the differentiating cell. I investigated the importance of mitochondria in CPC function and found that mitochondrial biogenesis and network expansion occur during lineage commitment, and blocking mitochondrial expansion along the tubulin network leads to impaired differentiation.
Aging is associated with accumulation of mitochondrial DNA (mtDNA) mutations. I investigated the consequences of mtDNA mutations on CPC function using mice with a proofreading-defective mitochondrial polymerase gamma (POLG) enzyme. I demonstrated that acquisition of mtDNA mutations impairs CPC survival, proliferation, and differentiation.
Autophagy is a process by which long-lived proteins and organelles are engulfed by autophagosomes for delivery to lysosomes for degradation. Mitophagy is the selective removal of dysfunctional mitochondria and is involved in mitochondrial quality control. As cells age, mitophagy is necessary to clear defective mitochondria to prevent their accumulation. Not much is known about mitophagy in CPCs. Parkin is an E3 ubiquitin ligase that ubiquitinates proteins on the outer mitochondrial membrane to facilitate mitophagy. Mitophagy receptors such as BNIP3, NIX, and FUNDC1 can also mediate mitophagy independently of Parkin and ubiquitination.
POLG CPCs have increased mitophagy, but this is not enough to rescue their impaired function. POLG CPCs have intact mitophagy in response to acute stress, but have impaired mitophagy in response to differentiation. I found that gene expression of NIX and FUNDC1 increased during differentiation and likely mediate mitophagy in CPCs.
Parkin promotes removal of damaged mitochondria in the myocardium in response to acute stress. I investigated whether Parkin-mediated mitophagy plays a role in clearing damaged mitochondria in the hearts of aging POLG mice. Modifying Parkin levels by cardiac-specific overexpression or genetic ablation did not alter autophagy and cardiac function. These results suggest that Parkin-mediated mitophagy does not play a role in clearing mitochondria with mtDNA mutations.
My findings demonstrate that mitochondrial quality control is essential for cell homeostasis and survival. It is critical to understand mechanisms regulating mitophagy in order to improve regenerative potential of CPCs and identify potential targets for heart disease.