Mitochondrial Paradigm for Degenerative Diseases, Aging and Cancer:

Ancient Origins and Mitochondrial Diseases

Douglas C. Wallace, Ph.D.

Center for Molecular and Mitochondrial Medicine and Genetics (MAMMAG)

University of California, Irvine

Irvine, CA, USA

Life requires both structure and energy.  Yet most modern biomedical research has focused on tissue-specific differences and the Mendelian genes that encode these differences.  The role of mitochondrial energy production and the mitochondrial genome in health and disease has been largely ignored.  

The mitochondria produce most of the energy for our cells as ATP to do work and heat to maintain our body temperatures.  They also generate most of the endogenous reactive oxygen species (ROS) as a toxic by product of respiration and encompass a mitochondrial self-destruct system, the mitochondrial permeability transition pore (mtPTP), which kills a cell with defective mitochondria when energy output declines and oxidative stress increases.

The mitochondrial genome consists of approximately 1500 genes, 37 encoded by the maternally-inherited mitochondrial DNA (mtDNA) and the remainder dispersed across the chromosomes.  The mtDNA encodes a 12S and 16S rRNA, 22 tRNAs and 13 proteins (ND1, 2, 3, 4L, 4, 5, 6; cytb, COI, II, III; and ATP6&8), all key subunits of the mitochondrial energy generating system oxidative phosphorylation (OXPHOS).  Each cell contains 1000s of mtDNAs, and the mtDNA has a very high mutation rate due to chronic ROS exposure.  This results in cells accumulating a mixture of mutant and normal mtDNAs, a state known as heteroplasmy. As the percentage of mutant mtDNAs increases, energy output declines and ROS production increases, ultimately killing the cell.  When enough cells in a tissue are lost, symptoms ensue.

Inherited mtDNA mutations have now been linked to all of the clinical symptoms seen in the age-related degenerative diseases including blindness, deafness, dementia, movement disorders, cardiovascular disease, muscle weakness, renal dysfunction, diabetes mellitus, cancer, etc.  Moreover, all mtDNA diseases have a delayed onset and progressive course.  This is now understood to result from the interaction between inherited and somatic mitochondrial mutations.  Inherited mitochondrial mutations predispose to disease, but somatic mtDNA mutations further erode mitochondrial function in post-mitotic tissues until the cell dies.  Thus the accumulation of somatic mtDNA mutations provides the “aging clock” for age-related diseases.   That mitochondrial ROS drives mitochondrial decline has been confirmed by showing that reducing mitochondrial ROS production in Drosophila extends life span and that targeting the antioxidant enzyme catalase to the mouse mitochondria increases life span.

Type II diabetes is an example of a mitochondrial age-related degenerative disease.  Family studies have linked Type II diabetes to both mtDNA rearrangement and base substitution mutations. The base substitution mutation at nucleotide pair (np) 3243 (A to G) in the tRNA^Leu(UUR) gene is the most common known genetic cause of Type II diabetes.  Patients that harbor 10 to 50% of the A3243G mutation develop Type II diabetes, but those with higher percentages of the mutation develop cardiomyopathy and/or the MELAS syndrome. Mitochondrial gene expression profiling using the MITOCHIP cDNA microarray has shown that the phenotypic shifts associated with small incremental changes in mtDNA genotype are the result of abrupt changes is the expression of arrays of mitochondrial genes. 

Human mtDNAs encompass a broad range of sequence polymorphisms.   All of this variation can be assembled in a single phylogenetic tree, rooted in Africa about 200,000 years before present (YBP) and radiating into Eurasia about 65,000 YBP and Siberia about 40,000 YBP.  Every time humans succeeded in colonizing a new climatic zone, there was a major reduction in mtDNA variation, with only a few mtDNAs succeeding in founding the mtDNA lineages that radiated into the new environments.  It now appears that mtDNA mutations arose in these founder mtDNAs which shifted mitochondrial energy allocation from primarily ATP in the tropics to increasing heat production in the temperate and arctic zones, permitting adaptation to the increased cold of higher latitudes.    The reduced ATP production of these mutations increases individual sensitivity energy deficiency diseases. However, these same mutations also reduce mitochondrial ROS production and are thus protective of aging and certain age-related diseases.

Analysis of the accumulation of somatic mtDNA base substitution mutations with age has revealed that certain mutations, particularly those of the mtDNA control region (CR), can be tissue specific.  For example the T414G mutation of the mtDNA L-strand promoter is present in fibroblasts and muscle, but absent in brain.  However, the tissue-specificity of these mutations can change in degenerative diseases. The T414G mutation, while absent in normal brains, in present in 65% of AD brains. Other regulatory mutants are also increased in AD brain. Thus, the accumulation of certain somatic mtDNA mutations may be important in etiology of a variety of degenerative diseases.

Cancer is also an age-related disease, and somatic and germline mtDNA mutations have now been linked to certain cancers.  For example, mutations in the mtDNA COI gene have been found to be enriched in prostate cancer.  Replacement of the prostate cancer cell line PC3 mtDNA with a normal mtDNA suppresses tumor growth while replacement with a mtDNA harboring a known pathogenic mutation greatly enhances tumor growth.  The increased tumor growth is associated with increased mitochondrial ROS production, and ROS is known to be mitogenic.  Therefore mitochondrial defects that increase ROS may be an important factor in driving neoplastic transformation.

Thus, defects in mitochondrial energy production can explain many puzzling features of age-related diseases. Consequently, the mitochondrial paradigm provides a bold new approach for elucidating the causes and developing treatments for the common age-related disorders.