Liza A. Pon, PhD
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.
Hirabayashi Y, Kwon SK, Paek H, Pernice WM, Paul MA, Lee J, Erfani P, Raczkowski A, Petrey DS, Pon LA, Polleux F. ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons. Science. (2017) 358:623-630. PMID: 29097544.
Pernice WM, Vevea JD, Pon LA. A role for Mfb1p in region-specific anchorage of high-functioning mitochondria and lifespan in Saccharomyces cerevisiae. Nat Commun. (2016) 7:10595. PMID: 26839174; PMCID: PMC4742906.
Higuchi-Sanabria R, Charalel JK, Viana MP, Garcia EJ, Sing CN, Koenigsberg A, Swayne TC, Vevea JD, Boldogh IR, Rafelski SM, Pon LA. Mitochondrial anchorage and fusion contribute to mitochondrial inheritance and quality control in the budding yeast Saccharomyces cerevisiae. Mol Biol Cell. (2016) 27:776-87. PMID: 26764088; PMCID: PMC4803304.
Vevea JD, Garcia EJ, Chan RB, Zhou B, Schultz M, Di Paolo G, McCaffery JM, Pon LA. Role for Lipid Droplet Biogenesis and Microlipophagy in Adaptation to Lipid Imbalance in Yeast. Dev Cell. (2015) 35:584-99. PMID: 26651293; PMCID: PMC4679156.
Wolken DM, McInnes J, Pon LA. Aim44p regulates phosphorylation of Hof1p to promote contractile ring closure during cytokinesis in budding yeast. Mol Biol Cell. (2014) 25:753-62. PMID: 24451263; PMCID: PMC3952846.
Higuchi R, Vevea JD, Swayne TC, Chojnowski R, Hill V, Boldogh IR, Pon LA. Actin dynamics affect mitochondrial quality control and aging in budding yeast. Curr Biol. (2013) 23:2417-22. PMID: 24268413; PMCID: PMC3932488. (This article was highlighted in a Rapid Dispatch in Current Biology and was selected as an F1000Prime paper by the Faculty of 1000.)
Crider DG, García-Rodríguez LJ, Srivastava P, Peraza-Reyes L, Upadhyaya K, Boldogh IR, Pon LA. Rad53 is essential for a mitochondrial DNA inheritance checkpoint regulating G1 to S progression. J Cell Biol. (2012) 198:793-8. PMID: 22927468; PMCID: PMC3432762. (featured article)
Swayne TC, Zhou C, Boldogh IR, Charalel JK, McFaline-Figueroa JR, Thoms S, Yang C, Leung G, McInnes J, Erdmann R, Pon LA. Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast. Curr Biol. (2011) 21:1994-9. PMID: 22119524; PMCID: PMC3237857. (This article was highlighted in a Rapid Dispatch in Current Biology.)
McFaline-Figueroa JR, Vevea J, Swayne TC, Zhou C, Liu C, Leung G, Boldogh IR, Pon LA. Mitochondrial quality control during inheritance is associated with lifespan and mother-daughter age asymmetry in budding yeast. Aging Cell. (2011) 10:885-95 PMID: 21726403; PMCID: PMC3173513.
Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon LA, Schon EA. Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol. (2009) 175:1810-6. PMID: 19834068; PMCID: PMC2774047.
García-Rodríguez LJ, Crider DG, Gay AC, Salanueva IJ, Boldogh IR, Pon LA. Mitochondrial inheritance is required for MEN-regulated cytokinesis in budding yeast. Curr Biol. (2009) 19:1730-5. PMID: 19818621; PMCID: PMC2783229.
Huckaba TM, Lipton T, and Pon LA Roles of type II myosin and a tropomyosin isoform in retrograde actin flow in budding yeast. (2006) J. Cell Biol. 175:957-969. PMID: 17178912 (This article is featured in a Rapid Dispatch in Current Biology.)
Huckaba TM, Gay A, Pantalena LF, Yang H-C and Pon LA Live cell imaging of the assembly, disassembly and actin cable-dependent movement of endosomes and actin patches the yeast Saccharomyces cerevisiae. (2004) J. Cell Biol., 167:519-530. PMID: 15534003 (featured article)