- Restrictions on Access:
- Open Access.
- Metabolic disorders and aging-related diseases are characterized by an accumulation of dysfunctional mitochondria and a gradual decline of the aging organism. Mitophagy, the selective degradation of mitochondria, is required for clearing damaged mitochondria. A decrease in mitophagy is observed with aging and is associated with an increase in aging-related diseases, but the mechanism of this is uncertain. Cardiolipin (CL) is a mitochondria-specific phospholipid that is necessary for optimal mitochondrial function. CL remodeling is required for the maturation of CL into healthy tetra-linoleoyl CL. However, pathological remodeling by ALCAT1, an acyltransferase located at the mitochondria-associated membrane, occurs in response to oxidative stress and aging. This remodeling results in dysfunctional mitochondria with leaky electron transport chain and increased oxidative stress. However the mechanism by which CL remodeling leads to accumulation of dysfunctional mitochondria in aging-related diseases, such as cardiovascular disease, is unknown. The hypothesis is that CL remodeling associated with aging and oxidative stress reduces mitophagy, and links CL remodeling with accumulation of dysfunctional mitochondria. With a genetic model that silences CL maturation, CL remodeling is specifically required for the recognition of mitochondria by the autophagy machinery in mitophagy. The results demonstrate in an ALCAT1 knockout mouse model that blocking pathologic CL remodeling reduces vascular oxidative stress and renders mice resistant to obesity-induced hypertension. Lastly, the unexpected role of CL remodeling and mitochondrial dysfunction in cellular inflammatory response is explored. Unexpectedly, overexpression of ALCAT1 results in upregulation of type I interferon signaling secondary to mitochondrial DNA release into the cytoplasm. These data support the well-established link between oxidative stress and aging-related diseases and suggest involvement of pro-inflammatory mechanisms. Overall, the results show that pathological CL remodeling is an underlying mechanism that drives acceleration of oxidative stress and aging-related disease. Furthermore, they indicate that CL remodeling, specifically ALCAT1 inhibition, may be a druggable target to reduce the burden of oxidative stress and inflammatory response as well as aid in the clearance of dysfunctional mitochondria.
- Dissertation Note:
- Ph.D. Pennsylvania State University, 2016.
- Technical Details:
- The full text of the dissertation is available as an Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
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