Access Type

Open Access Dissertation

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Miriam M. Greenberg

Abstract

Cardiolipin (CL) is the signature phospholipid of mitochondria. CL and its remodeling exert critical roles in biological processes both inside and outside of mitochondria. CL abnormalities have been associated with various mitochondrial disorders and aging. Understanding the role of CL in mitochondrial physiology and cellular metabolism could provide valuable insights into cell biology and human health. Several metabolic alterations have been reported in CL-deficient cells, including accumulated lactate, decreased PDH activity, and decreased TCA cycle function. This dissertation connected these findings by showing abnormal NAD+ metabolism in various models lacking CL. Importantly, it shows that NAD+ supplementation improves mitochondrial function by increasing the NAD+/NADH ratio, which holds high potential in normalizing the metabolic abnormalities of CL-deficient models. A model generated from these findings, for the first time, explains the CL-associated metabolic alterations systematically. Mitochondrial physiology is highly associated with bioenergetics and metabolism. This thesis, for the first time, describes a comprehensive analysis of yeast mitochondrial physiology in response to mitochondrial challenges induced chemically, genetically, and physiologically, in the presence and absence of oxidizable CL. These findings provide important insights into mitochondrial biology and add value to the yeast Saccharomyces cerevisiae as an excellent model for studying mitochondrial disorders. The importance of CL remodeling is highlighted by Barth syndrome (BTHS), which is caused by disruptions of the tafazzin gene. Studies using yeast have revealed that deletion of the CL-specific phospholipase Cld1 rescues defects of the yeast tafazzin mutant taz1Δ. However, little is known about the functionality of Cld1. This thesis reported a large-scale genetic screen, in which various novel cellular processes were identified to be functionally important to cld1Δ. The findings pointed out several new directions for understanding the role of CL remodeling in BTHS. In summary, this thesis provides novel and fundamental understandings on the critical roles of CL and its remodeling in cellular metabolism, mitochondrial physiology, and other important biological processes.

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