Mitochondrial Physiology Network 10.9: 49-50 (2005) - download pdf

Inter-genomic cross talk between the mitochondria and nucleus in aging and cancer.

Keshav Singh

Dept. Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. - keshav.singh@roswellpark.org  

    As an important part of ‘free-radical theory of aging’ mitochondria play a fundamental role both as producers and targets of ROS. Mitochondrial DNA (mtDNA) is extremely susceptible to ROS damage compared to genomic DNA because of ROS production by the mitochondria, the absence of protective histones and limited DNA repair. Thus individuals accumulate mtDNA mutations as they age which leads to compromised mitochondrial function.

    To understand the biological consequences of mtDNA mutation accumulated during aging we have created mitochondrial gene knock out cell lines (r⁰). Our study suggests that r⁰ cells demonstrate characteristic features of cellular aging. Mitochondrial gene knock out r⁰ cells showed typical morphology associated with aging such as increased size and elongated appearance. They have increased senescence-associated b-Gal activity, lipofuscin pigment and plasminogen activator inhibitor-1 expression. Consistent with their decreased proliferation, the expression of mitotic cyclins was decreased and that of cdk inhibitors was increased. Retinoblastoma (Rb) hypophosphorylation and decreased telomerase activity were also noted. Using this cellular model and cybrid cell technology, we provide evidence that (1) inactivation of mitochondrial genes leads to chromosomal instability (CIN) that are present in a variety of human tumors and (2) mitochondrial gene knockout cells show transformed phenotype.  Our study also demonstrates that mitochondrial genetic status plays a key role in regulation of a multifunctional protein APE1 (also known as Ref1 or HAP1) involved in transcription and DNA repair in the nucleus and the mitochondria. Our study revealed that altered expression of APE1 in r⁰ cells and tumorigenic phenotype can be reversed by exogenous transfer of wild type mitochondria in r⁰ cells. Furthermore, we demonstrate that APE1 expression is altered in variety of primary tumors.  Taken together, these studies suggest that inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis and that APE1 mediates this process. Our study support the mitochondrial theory of aging and suggest that r⁰ cells can serve as an in vitro model for cellular aging.