Date of Award

8-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

Malia B. Potts, PhD

Committee

Mondira Kundu, MD, PhD; Joseph Opferman, PhD; Fatima Rivas, PhD; Zhaohui Wu, PhD

Abstract

Mitochondria are vital organelles that coordinate cellular energy homeostasis and also have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria through autophagy, a process called mitophagy, is critical for maintaining proper cellular function. Much of the research elucidating the mechanism and regulation of autophagy was performed in yeast cells, so there is still a lot of mystery surrounding how mitophagy is promoted and regulated in mammals in general and in different tissues. The most well understood mechanism involved in mitophagy is the PINK1-PARKN pathway. However, studies often rely on severe mitochondrial damage using CCCP that is considered non-physiological. To find novel regulators of mitophagy in mammalian cells, we used a previously published screen for autophagy regulators to identify the MEKK3-MEK5-ERK5 pathway as a potential regulator of mitophagy in the absence of exogenous damage. Here, I provide evidence that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. I confirm that the MEKK3-MEK5-ERK5 pathway is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis, confirming a selective role in basal mitochondrial degradation. Furthermore, inhibition of MEK5 or ERK5 in erythrocytes leads to defective mitochondrial elimination and impaired erythrocyte differentiation. In addition to finding a novel mitophagy promoting pathway, we also worked to discover a novel mitophagy inducing compound. There are several different mechanisms for mitophagy induction, so there is considerable interest in the field in identifying novel chemical modulators that promote the efficient removal of mitochondria through different pathways.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0002-3696-347X

DOI

10.21007/etd.cghs.2020.0512

2020-021-Craig-DOA.pdf (345 kB)
Declaration of Authorship

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