PhD, Case Western Reserve University
We are interested in the dynamic interplay between the intracellular distribution of mitochondria and cellular function. Mitochondria are not discrete or autonomous but form highly dynamic, interconnected networks whose biogenesis and structure are highly influenced by the needs of the cell. Mitochondria have a myriad of functions in addition to cellular energy production and play critical roles in cell cycle progression, differentiation, development, immune responses, lipid and calcium homeostasis, and apoptotic cell death. These diverse roles of mitochondria are intimately connected to the shape and position of this essential organelle. Thus it is not surprising that aberrant mitochondrial architecture has been associated with an ever-increasing number of diseases, including Alzheimer’s disease, Parkinson’s disease, diabetes and many cancers.
Mitochondrial tethers play a central role in maintaining mitochondrial architecture. Tethers exert spatial, temporal and contextual control over the cellular position of the organelle. In addition, tether-mediated interactions have been proposed to facilitate the exchange of lipid, calcium, and/or other small molecules between mitochondria and other membrane compartments, such as the ER and plasma membrane. While mitochondrial tethering is observed in cells from yeast to neurons, it is the least well understood and most overlooked of the activities that shape and position mitochondria. Thus, fundamental biological questions regarding mitochondrial tethers remain unanswered: 1) What is the molecular basis of mitochondrial tethering? 2) How are mitochondrial tethers regulated to properly position mitochondria to meet cellular needs? and 3) How do mitochondrial tethers both impact and respond to changes in mitochondrial and cellular function? We aim to address these questions using a combination of cell biological, genetic, biochemical, and biophysical approaches. Our comparative analysis of mitochondrial tethers in various cell types will provide a better molecular understanding of the mechanisms used to control the intracellular position of mitochondria. Thus, we will gain insight into strategies that can be used to modulate the position of mitochondria to influence cellular health and homeostasis.
Lackner LL. (2014) Shaping the dynamic mitochondrial network. BMC Biology 12:35. Link
Murley A, Lackner LL*, Osman C*, West M, Voeltz GK, Walter P and Nunnari J. (2013) ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast. eLife 2:e00422. *equal contribution. Link
Lackner LL. (2013) Determining the shape and cellular distribution of mitochondria: the integration of multiple activities. Current Opinion in Cell Biology 25:471-476. Review. Link
Lackner LL, Ping H, Graef M, Murley A, and Nunnari J. (2013) Endoplasmic reticulum associated mitochondria-cortex tether functions in the distribution and inheritance of mitochondria. PNAS 110:E458-E467. Link
Hoppins S, Collins SR, Cassidy-Stone A, Hummel E, DeVay RM, Lackner LL, Schuldiner M, Westermann B, Weissman JS, and Nunnari J. (2011) A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria. Journal of Cell Biology 195:323-340. Link
Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK. (2011) ER tubules mark sites of mitochondrial division. Science 334:358-362. Link
Mears JA, Lackner LL, Fang S, Ingerman E, Nunnari J, Hinshaw JE. (2011) Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nature Structural Molecular Biology 18:20-26. Link
Lackner LL, Nunnari J. (2010) Small molecule inhibitors of mitochondrial division: tools that translate basic biological research into medicine. Chemistry and Biology. 17:578-583. Review. Link
DeVay RM, Dominguez-Ramirez L, Lackner LL, Hoppins S, Stahlberg H, Nunnari J. (2009) Coassembly of Mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion. Journal of Cell Biology 186:793-803. Link
Lackner LL, Horner JS, Nunnari J. (2009) Mechanistic Analysis of a Dynamin Effector. Science 325:874-877. Link
Lackner LL, Nunnari J. (2009) The Molecular Mechanism and Cellular Functions of Mitochondrial Division. Biochimica et Biophysica Acta. 792:1138-44. Review. Link
Lee YJ, Lackner LL, Nunnari JM, Phinney BS. (2007) Shotgun Cross-Linking Analysis for Studying Quaternary and Tertiary Protein Structures. Journal of Proteome Research 6:3908-3917. Link
Lackner LL*, Hoppins S*, Nunnari J. (2007) The machines that divide and fuse mitochondria. Annual Review of Biochemistry. 76:751-80. Review. *equal contribution. Link