All ETDs from UAB

Advisory Committee Chair

Steven Pogwizd

Advisory Committee Members

Lufang Zhou

Adam Wende

Ganesh Halade

Suzanne Michalek

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mitochondria are abundantly present in metabolic active organs such as the heart. The presence of mitochondria are crucial to provide energy in the form of ATP, regulate calcium handling, facilitate cell fate, and are involved in metabolic modulation. In the process of generating ATP through oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS) as a side product. In the heart, mitochondria is a major source of ROS. Under normal conditions, ROS are kept at a physiologically relevant and healthy level. Unfortunately, excessive ROS levels during pathological states, such as pressure overload heart failure, appears as a threat to the whole organism. Since heart failure (HF) is a multifactorial disease, it is still unclear with regards to the specific damaging effects of mitochondrial-derived ROS during the development of the disease at different levels. We hypothesized that uncontrolled mitochondrial-derived ROS can disrupt mitochondrial dynamics and its network behavior in the diseased state. At the tissue and organ level, excessive mitochondrial- derived ROS can compromise heart function during HF. Using the ascending aortic constriction (AAC) model of pressure overload, we first demonstrated that HF mitochondrial clusters are less cooperative in mitochondrial network synchronization. In addition, the HF mitochondrial network ultrastructure was disrupted and thereby reduced excitability. Following that, we further showed that unwarranted oxidative stress drove cardiac remodeling and resulted in impaired cardiac function. Finally, we provided evidence that mitochondrial-targeted antioxidant such as Mitoquinone (MitoQ) treatment in pressure overload heart failure can dampen oxidative damage, restrict cardiac remodeling events, and partially upregulate SR calcium handling channels. More importantly, MitoQ restore cardiac function in pressure overload mice comparable to normal mice. We concluded that mitochondrial-derived ROS are detrimental to cardiac contractile function. MitoQ, a mitochondrial-targeted antioxidant treatment poses as a potential therapeutic intervention for HF.

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