| The process of aging is the decline of an organism's lifespan and is defined by changes at distinct levels of organizational structures: molecular, cellular, tissue level, and systemic. Aging increases the susceptibility for disease states that are less likely to occur earlier in life, suggesting that there are molecular pathways involved in both the process of aging and disease onset. By understanding genetic factors whose anomalous expression and changing function lead to aging and age-related diseases, we can better understand the biological process of aging and identify potential therapeutics for age-associated diseases.;The basis of my thesis is the study of transmembrane protein 135 ( Tmem135), whose anomalous expression leads to aging and age-related disease phenotypes. TMEM135 is a highly conserved protein that localizes to the outer membrane of mitochondria and other cellular vesicles. TMEM135 protein was recently characterized as a mitochondrial fission factor that has been implicated in longevity and aging. Previous studies have shown that a partial loss of function mutation in Tmem135 leads to age-associated retinal degeneration. However, the effect of Tmem135 overexpression has yet to be fully studied.;In Chapter 1, we examined the effect of Tmem135 overexpression in the adult mouse heart. The heart, like the retina, has high energy demands met largely by mitochondria. Perturbations in mitochondrial dynamics and functions have detrimental effects on such tissues. Specifically, transgenic overexpression of Tmem135 (Tmem135 TG) leads to fragmented mitochondria in vivo in the heart of adult mice. Tmem135 TG mice exhibit age-associated and disease phenotypes including hypertrophy and collagen accumulation in the heart. Furthermore, we found that the gene expression profiles of Tmem135 TG hearts resemble those of aged hearts. Finally, we showed that the activating transcription factor 4 (ATF4) branch of the unfolded proteins response (UPR) pathway is activated in Tmem135 TG hearts, which may be responsible for age-associated phenotypes in the heart.;In Chapter 2, we sought to identify factors that interact with Tmem135 to help further elucidate TMEM135 functions in the heart. We found that overexpression of Tmem135 on the mixed genetic background (FVB and C57BL6/J) leads to sudden death in some of the Tmem135 TG mice around the weaning age. We then compared the hearts of Tmem135 TG mice that are at high risk and low risk for sudden death to examine what changes in gene expression and metabolites are observed before sudden death. From these analyses, we found that pathways associated with energy production are affected. Finally, we used a genetic approach to identify modifiers of sudden early death caused by Tmem135 overexpression. We were able to identify a significant genetic association on chromosome 11 and multiple candidate genes in the region.;Our study indicates that mitochondrial dynamics are important for the maintenance of normal heart function and may have significant roles in the aging of the heart. We also identified molecular pathways that are affected by overexpression of Tmem135/increased mitochondrial fission, which may be important for understanding the cause of sudden death with heart failure. |
