Keynote Speaker

Actin dynamics regulate spatial mixing of mitochondria in dividing cells and

mitochondrial hobaurmeostasis in interphase cells

Mitochondria form interconnected and dynamic networks that can rapidly remodel in response to changes in cellular physiology. This remodeling is dependent on the cellular cytoskeleton. In interphase, mitochondria are actively transported along microtubules, driven by the coordinated activities of the molecular motors cytoplasmic dynein and kinesin. In dividing cells, mitochondrial dynamics become more fully dependent on the actin cytoskeleton and the myosin motor Myo19. We are using live cell imaging to explore the interactions of mitochondria with actin, leading to the discovery of actin cycling, in which a dynamic wave of actin filament polymerization that cycles through mitochondrial networks. In mitosis, actin cycling regulates the spatial mixing of mitochondria leading to the symmetrical division of mitochondrial genotypes between daughter cells. In contrast, in interphase cells, we find that actin cycling facilitates mitochondrial content mixing by enhancing fission. We hypothesize that robust fission/fusion dynamics facilitate complementation, effectively maintaining the overall health of the mitochondrial network. In support, inhibition of actin cycling leads to a reduction in mitochondrial membrane potential, accompanied by decreased oxygen consumption, lower levels of cellular ATP, and increased cellular ROS. Thus, we propose that the cyclic assembly of actin on/off mitochondria promotes dynamic network remodeling and content mixing, serving as an essential mechanism regulating mitochondrial network homeostasis.

Myron Levine was a founder of the CMB Program and Director from 1974 to 1990. The program was initiated to provide a meeting ground for faculty scattering among different departments across the campus who had overlapping research interests in the rapidly developing fields of cellular and molecular biology. The continuing success of the program over nearly four decades is a confirmation of wisdom of its founders. During his long tenure as Director, Mike was particularly sensitive to the needs of CMB students. While always attentive to the goals of the program, his flexibility facilitated positive problem-solving, and his wise counsel helped students overcome personal and academic difficulties to succeed in the program. Mike was very proud of the continued success of CMB under the Robert Bender, Dave Engelke and Jessica Schwartz, and he considered the program to be one of his most important achievements.

Mike carried out his undergraduate work at Brooklyn College in New York City. A summer research program at Cornell University in Ithaca was influential in his commitment to biological research. A faculty advisor encouraged him to apply to graduate school in the Biology Department at the University of Indiana in Bloomington, which was then at the forefront of genetics research. His teachers there included Herman Muller and Tracy Sonneborn. As a postdoctoral fellow with Salvador Luria, who was later to win the Nobel Prize, Mike attended the famed Phage Group meetings at Cold Spring Harbor Laboratory in the 1950s and 60s. The accommodations at the Laboratory were primitive at that time but the intellectual atmosphere was rarefied, and the Levine family spent several memorable summers there.

Mike joined the Department of Human Genetics at the University of Michigan in 1961. The early work in his laboratory focused on the genetic regulation of lysogeny in bacteriophage P22, which has a genome of 44 kb encoding 64 genes. With postdoctoral fellow Hamilton Smith, who later went on to win a Nobel Prize, he used pulse–labeling to identify the sequential activation and repression of phage genes during the establishment of lysogeny, work that was published in Science and considered by Mike as some of his best. Smith’s recollection of his years in Mike’s lab can be heard in an interview at the Cold Spring Harbor Laboratory oral history web site. As a Ph. D. student with Mike, David Botstein used temperature-sensitive phage mutants to dissect the intermediates in phage replication. Botstein went on to chair the genetics departments at Stanford and Princeton. The Levine lab also carried out cell-free assembly of pre-formed tail-less heads and head-less tails into active phage. He reviewed the work of this period in an article on Phage Morphogenesis in the Annual Review of Genetics, Vol. 3, 1969, that still reads well today.

In the 1970s and 80s, Mike applied similar logic to dissect the process of latent neuronal infection by the Herpes virus, which has a 150 kb genome encoding 100 genes. With students and postdoctoral fellows Fred Homa, Roz Sandri-Goldin and Al Goldin, the laboratory studied viral replication and the establishment of latency. In an interdisciplinary collaboration with neurologist David Fink and virologist Joe Glorioso, this virus was developed as a carrier for gene therapy, taking advantage of the natural tropism of the virus for neuronal ganglia. This work was continued in the Fink and Glorioso laboratories, leading to delivery of the human proenkephalin gene for treatment of chronic pain by administration of herpes virus through the skin (Ann. Neurol. 2011). More than 25 years after initiation of the work, clinical trials are now in progress.

In addition to his contributions to education and research, with publication of more than 120 articles, Mike served the scientific community on editorial and review panels, as Editor of the Journal of Virology, and member and chair of the NIGMS committee on the Genetic Basis of Disease. He was Acting Chair of the Department of Human Genetics for 3 terms and was honored with the UM Distinguished Faculty Achievement Award, the Distinguished Biomedical Lecture, and the Annual CMB Myron Levine Lecture. He served as a member of the Wallenberg Executive Committee for more than 20 years.

Mike was greatly valued by his faculty colleagues. At faculty meetings in the Department of Human Genetics, his was a voice of reason – clear, insightful, dispassionate and humane, a model of the academic virtues. People leaned forward to hear his quiet, measured contributions. One of my first evenings in Ann Arbor was spent at a CMB student/faculty get-together in the Levines’ home on Hillsdale. The room was full, with students sitting and standing everywhere. The atmosphere was warm and collegial, imbued with the graceful hospitality that Mike and Bobbie so generously shared with the University community. After his retirement in 1996, Mike remained active as an Emeritus Professor, continuing to participate in many CMB and Human Genetics functions. For more than 40 years, Mike Levine made unique contributions to the quality of academic life at the University of Michigan. He will be long remembered and deeply missed.

Written by Miriam Meisler, Myron Levine Professor of Human Genetics