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H. Peter Zassenhaus, Ph.D.

Professor Emeritus
Molecular Microbiology and Immunology


Research in my laboratory centers around investigations into the molecular mechanisms of aging. One of the major ideas about the cause of aging postulates that mitochondria slowly lose their capacity to generate energy as individuals age. It is known that the frequency of mitochondrial DNA mutations rises exponentially with aging. It has also been shown that in many tissues mitochondrial respiratory capacity declines with age. The decrease in ATP synthesis compromises cellular physiological function leaving the cell vulnerable to stress and less able to repair damage -culminating in senescence. One major source of that stress derives from the mitochondria itself ' namely reactive oxygen species that are natural byproducts of respiration. It is thought that the age-related increase in mtDNA mutations results in higher levels of oxidative stress which, in turn, not only causes damage to proteins and other cellular macromolecules, but also, in a Catch 22, leads to further elevations in the levels of mtDNA mutations. This viscous circle ultimately culminates in either cell death or the vulnerability to late-onset diseases like Alzheimer's, Parkinson's, and Type II Diabetes.

Fig 1 ZassenhausFig 2 Zassenhaus

(Fig. 1) The top mouse is a 6 week old transgenic in congestive heart failure. The bottom mouse is his normal brother. (Fig. 2) Three transgenic mice with dilated cardiomyopathy. Note that the hearts look like blown up balloons.

Fig 3 Zassenhaus

The Jewel of the Nile. The right heart was removed from a 6 month old transgenic mouse; the one on the left is from a same aged control littermate. Note the enlarged atria -- the rabbit ears. The ventricles are also enlarged.

We are testing the above scenario by studies of transgenic mouse models for mitochondrial based disease. We have created a transgenic mouse, which rapidly accumulates mutations only in the mitochondrial DNA of the heart. Figure 1 shows one of these mice next to a control littermate at about 6 weeks of age. These mice develop cardiac disease early in life, which often is manifested as congestive heart failure. At the time this mouse developed severe heart failure, its cardiac mitochondria had a frequency of mitochondrial DNA mutations that would normally be found in an 80-year-old person. Thus, these mice have old mitochondria in a young body. As mutation frequencies rise, their hearts dilate in order to maintain cardiac performance Figure 2. An enlarged heart (Figure 3) is also characteristic in many cases of human heart disease. We are characterizing these transgenic mice at the molecular level to discover how the rising frequency of mitochondrial DNA mutations leads to heart disease.

Surprisingly, our studies so far suggest that whatever the molecular mechanism is, it does not appear to involve a decline in the ability of the mitochondria to generate ATP. Neither, does it appear to result from an increase in oxidative stress. Our current hypothesis is that the mutations lead to a dysregulation of the mitochondrial permeability transition pore which is intimately linked to the regulation of apoptosis and, thus, cell survival. Perturbations in the function of that pore are hypothesized to communicate to the nucleus via signal transduction pathways involving nuclear receptor – possibly the peroxisome-proliferator activated receptors.

Labs and Facilities

Peter Zassenhaus, Ph.D.

Annie Hughes, Research Assistant, Sr.


Bensch KG, Mott JL, Chang SW, Hansen PA, Moxley MA, Chambers KT, de Graaf W, Zassenhaus HP, Corbett JA.
Selective mtDNA mutation accumulation results in beta-cell apoptosis and diabetes development.
Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E672-80. Epub 2009 Jan 21.
Pubmed Abstract Link: 19158322

Dubec SJ, Aurora R, Zassenhaus HP.
Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release.
Rejuvenation Res. 2008 Jun;11(3):611-9.
Pubmed Abstract Link: 18593279

Bensch KG, Degraaf W, Hansen PA, Zassenhaus HP, Corbett JA.
A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in beta-cells.
Diabetes Obes Metab. 2007 Nov;9 Suppl 2:74-80.
Pubmed Abstract Link: 17919181

Mott JL, Zhang D, Chang SW, Zassenhaus HP.
Mitochondrial DNA mutations cause resistance to opening of the permeability
transition pore.
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):596-603.
Pubmed Abstract link: 16829230

Mott JL, Zhang D, Zassenhaus HP.
Mitochondrial DNA mutations, apoptosis, and the misfolded protein response.
Rejuvenation Res. 2005 Winter;8(4):216-26.
Pubmed Abstract link: 16313221

Zhang D, Mott JL, Chang SW, Stevens M, Mikolajczak P, Zassenhaus HP.
Mitochondrial DNA mutations activate programmed cell survival in the mouse heart.
Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2476-83.
Pubmed Abstract link: 15840907

Zhang D, Ezekiel UR, Chang SW, Zassenhaus HP.
Gene expression profile in dilated cardiomyopathy caused by elevated frequencies of mitochondrial DNA mutations in the mouse heart.
Cardiovasc Pathol. 2005 Mar-Apr;14(2):61-9.
Pubmed Abstract link: 15780797

Mott JL, Zhang D, Freeman JC, Mikolajczak P, Chang SW, Zassenhaus HP,
Cardiac disease due to random mitochondrial DNA mutations is prevented by cyclosporin A.
Biochem Biophys Res Commun. 2004 Jul 9;319(4):1210-5.

Zhang D, Mott JL, Farrar P, Ryerse JS, Chang SW, Stevens M, Denniger G, Zassenhaus HP.
Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy. Cardiovasc Res. 2003 Jan;57(1):147-57.

Mott JL, Zhang D, Stevens M, Chang S, Denniger G, Zassenhaus HP.
Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations.
Mutat Res. 2001 Mar 1;474(1-2):35-45.

Mott JL, Denniger G, Zullo SJ, Zassenhaus HP.
Genomic structure of murine mitochondrial DNA polymerase-gamma.
DNA Cell Biol. 2000 Oct;19(10):601-5.

Zhang D, Mott JL, Chang SW, Denniger G, Feng Z, Zassenhaus HP.
Construction of transgenic mice with tissue-specific acceleration of mitochondrial DNA mutagenesis.
Genomics. 2000 Oct 15;69(2):151-61.

Li H, Zassenhaus HP.
Phosphorylation is required for high-affinity binding of DBP, a yeast mitochondrial site-specific RNA binding protein.
Curr Genet. 2000 Jun;37(6):356-63.

Chang SW, Zhang D, Chung HD, Zassenhaus HP.
The frequency of point mutations in mitochondrial DNA is elevated in the Alzheimer's brain.
Biochem Biophys Res Commun. 2000 Jun 24;273(1):203-8.

Mott JL, Zhang D, Farrar PL, Chang SW, Zassenhaus HP.
Low frequencies of mitochondrial DNA mutations cause cardiac disease in the mouse.
Ann N Y Acad Sci. 1999;353-7.

Li H, Zassenhaus HP.
Purification and characterization of an RNA dodecamer sequence binding protein from mitochondria of Saccharomyces cerevisiae.
Biochem Biophys Res Commun. 1999 Aug 11;261(3):740-5.

Margossian SP, Li H, Zassenhaus HP. and Butow RA.
The DExH box protein Suv3p is a component of a yeast mitochondrial 3'-to-5' exoribonuclease that suppresses group I intron toxicity.
Cell. 1996 Jan 26;84(2):199-209.

Ezekiel UR, Towler EM, Wallis JW, Zassenhaus HP.
Evidence for a nucleotide-dependent topoisomerase activity from yeast mitochondria.
Curr Genet. 1994 Dec;27(1):31-7.

Ezekiel UR, Zassenhaus HP.
Evidence for a site-specific endonuclease in yeast mitochondria which recognizes the sequence 5'GCCGGC.
Biochem Biophys Res Commun. 1994 May 30;201(1):208-14.

Zassenhaus HP. and Denniger G.
Analysis of the role of the NUC1 endo/exonuclease in yeast mitochondrial DNA recombination.
Curr Genet. 1994 Feb;25(2):142-9.

Hofmann TJ, Min J, Zassenhaus HP.
Formation of the 3' end of yeast mitochondrial mRNAs occurs by site-specific cleavage two bases downstream of a conserved dodecamer sequence.
Yeast. 1993 Dec;9(12):1319-30.

Min J, Zassenhaus HP.
A nucleoside triphosphate-regulated, 3' exonucleolytic mechanism is involved in turnover of yeast mitochondrial RNAs.
J Bacteriol. 1993 Oct;175(19):6245-53.

Ezekiel UR, Zassenhaus HP.
Localization of a cruciform cutting endonuclease to yeast mitochondria.
Mol Gen Genet. 1993 Sep;240(3):414-8.

Min J, Zassenhaus HP.
Identification of a protein complex that binds to a dodecamer sequence found at the 3' ends of yeast mitochondrial mRNAs.
Mol Cell Biol. 1993 Jul;13(7):4167-73.

Min J, Heuertz RM, Zassenhaus HP.
Isolation and characterization of an NTP-dependent 3'-exoribonuclease from mitochondria of Saccharomyces cerevisiae.
J Biol Chem. 1993 Apr 5;268(10):7350-7.


NIH R21/R33
"Dengue diagnostics using a novel peroxidase chain reaction (PxCR)"