Mitochondria have emerged as central regulators of aging, cell death, energy mobilization, oxidative stress management and calcium homeostasis. Since mitochondria are essential organelles that can only be produced from pre-existing mitochondria, these organelles must be inherited from mother to daughter cells for daughter cell survival. Our research focuses on cytoskeletal dynamics and function in control of mitochondrial motility during inheritance, and the role of this process on cell cycle progression and lifespan control. The model system that we use for most of our studies is the budding yeast, Saccharomyces cerevisae. We are also studying mitochondrial distribution and function in neuronal cell models for the age-associated neuronal degenerative disease, familial Alzheimer's Disease.
Although microtubules serve as tracks for long distance mitochondrial movement in the neuronal axon and other cells, the actin cytoskeleton is used for mitochondrial movement in budding yeast and in specialized regions in polarized mammalian cells including the neuronal synapse and the immunological synapse. Our previous studies revealed mechanisms for bi-directional movement of mitochondria, which relies on actin cables, bundles of F-actin that align along the mother-bud axis, the Arp 2/3 complex, actin polymerization, and actin cable dynamics. Current efforts focus on the mechanism of action of a newly identified Ras-like actin cable regulator, and how actin cable dynamics and function change as a function of age.
There are many checkpoints that regulate cell cycle progression in response to inheritance of the nucleus. Recently, we identified two checkpoints that inhibit cell cycle progression when there are defects in mitochondrial inheritance The mitochondrial inheritance checkpoint that inhibits cell cycle progression at cytokinesis when there are defects in mitochondrial inheritance. This is mediated by a conserved cell cycle checkpoint regulator, the Mitotic Exit Network. The other checkpoint, the mitochondrial DNA (mtDNA) inheritance checkpoint, inhibits progression from G1 to S phase of the cell division cycle when mtDNA in not inherited by daughter cells. This checkpoint is regulated by Rad53p, a component of the DNA Damage Checkpoint signaling pathway. It responds to loss of DNA in the organelle and not to genes encoded by the DNA. Current efforts focus on the sensing mechanism for detecting defects in the inheritance of mitochondria and mtDNA and how this information is transmitted to the signaling pathways that regulate cell cycle progression.
Equally important, we find that the fittest mitochondria, those with the lowest reactive oxygen species (ROS), are preferentially inherited to daughter cells and that mutations that inhibit mitochondrial inheritance produce defects in the inheritance of the fittest mitochondria and premature aging. Recent studies indicate that this occurs in part by cytoskeleton-dependent preferential transport and anchorage of the fittest mitochondria in daughter cells and that increasing mitochondrial quality in daughter cells extends lifespan in budding yeast. Current studies focus on the role of mitochondrial fusion and fission mediators and other quality control mechanisms in this process, and how mitochondrial motility, cytoskeletal interactions and quality control change with age.The Pon Lab
1. Higuchi, R., Vevea, J.D., Swayne, T.C., Chojnowski, R., Hill, V., Boldogh, I.R., and Pon, L.A.
(2013) Actin dynamics affect mitochondrial quality control and aging in budding yeast. Curr Biol. 23:2417-22
2. Crider, D.G., *Garcia-Rodriguez, L.J., Peraza Reyes, C.L., Srivastrava, P., Upadhyaya, K., Boldogh, I.R., and Pon, L.A.
(2012) Rad53 is essential for a mitochondrial DNA inheritance checkpoint regulating G1 to S progression, J. Cell Biol. 198:793-798.
3. *Swayne, T.C., *Zhou, C., *Boldogh, I.R., Charalel, J.R., McFaline-Figueroa, J.R., Thoms, S., Yang, C., Leung, G. McInnes, J., Erdmann, R. and Pon, L.A.
(2011) Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast, Curr Biol. 21:1994-1999
4. McFaline-Figueroa, J.R., Zhou, C., Swayne, T.C, Vevea, J.D., Liu, C., Boldogh, I.R, and Pon, L.A.
(2011) Retention of mitochondria in the bud tip contributes to asymmetric segregation of age in budding yeast, Aging Cell. 2011 10:885-895.
5. Garcia-Rodriguez LJ, Crider DG, Gay AC, Salanueva IJ, Boldogh IR, Pon, L.A.
(2009) Mitochondrial inheritance is required for MEN-regulated cytokinesis in budding yeast. Curr Biol. 19:1730-5.
6. Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon, L.A.
, Schon EA. (2009) Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol. Epub 2009 Oct 15.
7. Garcia-Rodriguez, L.J., Gay, A.C., and Pon, L.A.
(2007) Puf3p is a mitochondrial protein that regulates mitochondrial biogenesis and inheritance, J. Cell Biol., 76:197-207.
8. Mitochondria, 2nd Edition. Methods in Cell Biology. (2007) Pon, L.A.
and E.A Schon, editors. Elsevier Press.
9. Huckaba, T.M., Lipton, T., and Pon, L.A.
(2006) Roles of type II myosin and a tropomyosin isoform in retrograde actin flow in budding yeast, J. Cell Biol.,175:957-69.
10. Fehrenbacher, K., Boldogh, I.R., and Pon, L.A.
(2005) A role for Jsn1p in recruiting Arp2/3 complex to mitochondria in budding yeast Mol. Biol. Cell 16:5094-5102.
12. Huckaba, T.M., Gay, A.C., Pantalena, L.F., Yang, H-C., and Pon, L.A.
(2004) Live cell imaging of the assembly, disassembly, and actin cable-dependent movement of endosomes and actin patches in the budding yeast, Saccharomyces cerevisiae. J. Cell Biol. 167:519-30.
13. Fehrenbacher, K.L., Yang, H-C., Gay, A.C., Huckaba, T.M., andPon, L.A.
(2004) Live cell imaging of mitochondrial movement along actin cables in budding yeast. Curr Biol. 14:1996-2004.
14. Boldogh, I.R., Ramcharan, S., and Pon, L.A.
(2004) A type V myosin (Myo2p) and a Rab-like G-protein (Ypt11p) are required for retention of newly inherited mitochondria in yeast cells during cell division. Mol. Biol. Cell. 15:3994-4002.
15. Boldogh, I.R., Nowakowski, D., Yang, H-C., Chung, H., Karmon, S., Royes, P., and Pon, L.A.
(2003) A protein complex containing Mdm10p, Mdm12p and Mmm1p links mitochondrial membranes and DNA to the cytoskeleton-based segregation machinery. Mol Biol Cell. 14:4618-4627.
16. Yang, H-C., and Pon, L.A.
(2002) Actin cable dynamics in budding yeast. Proc Natl Acad Sci, USA. 99:751-756.
17. Boldogh, I., Nowakowski, W.D., Yang, H-C., Karmon, S.L., Hayes, L., Yates, J., and Pon, L.A.
(2001) The Arp2/3 complex is required for actin-based mitochondrial motility in yeast. Proc Natl Acad Sci, USA. 98:3162-3167.
Honors and Awards
1987 - 90
National Research Service Award for Post-doctoral Research from the National Institutes of General Medicine.1992 - 95
Junior Faculty Research Award from the American Cancer Society.1992 - 95
Basil O'Connor Starter Scholar Research Award from the March of Dimes.1996
Gender Equity Award for promoting a gender-fair environment for the education and training of women physicians and assuring equal opportunity for women and men to study and practice medicine. Awarded by the American Medical Women's Association, Inc.2000 - 01
Editor, Methods in Cell Biology2000 - 02
Chair and Co-Chair for the Gordon Research Conference, "Plant and Fungal Cytoskeleton"2000 - 04
Study Section Member, for Cell Development and Function-4 (CDF-4) NIH/NIGMS2000 - 05
Editorial Board of Cell Motility and the Cytoskeleton2001
Gender Equity Award for promoting a gender-fair environment for the education and training of women physicians and assuring equal opportunity for women and men to study and practice medicine. Awarded by the American Medical Women's Association, Inc.2002
The Charles W. Bohmfalk Memorial Prize for Distinguished Contributions to Teaching in recognition of Excellence in Teaching during the Pre-Clinical Years at Columbia University College of Physicians and Surgeons.2006 - 07
Editor, Methods in Cell Biology2006 - 11
Review Committee Member, Biomedical Research and Training (BRT-A) review committee, NIH/NIGMS2010 - 11
Chair, Biomedical Research and Training (BRT-A) review committee, NIH/NIGMS2008 - Present
Editorial Board of the International Journal of Cell Biology.2013 – Present
Editorial Board of Microbial Cell.