Nunnari delivers dynamic talk about mitochondrial biology
By Jeffrey Stumpf
University of California, Davis professor Jodi Nunnari, Ph.D., communicated her enthusiasm for mitochondrial biology in a captivating seminar June 25 at NIEHS.
Hosted by trainees as part of the Laboratory of Molecular Genetics (LMG) Fellows Invited Guest Lecture series, Nunnari wowed the audience with microscopy and crystallography data from her group’s exciting new discoveries in mitochondrial dynamics. Nunnari and her lab explore how the maintenance of mitochondrial DNA (mtDNA) affects mitochondrial dynamics and, ultimately, health and disease.
NIEHS has a long-standing interest in understanding genetic and environmental factors that alter mitochondrial behavior and impact cellular energy production. Containing small circular DNA nucleoids, mitochondria actively join and divide from other mitochondria, independent of the cell cycle, a process commonly called mitochondrial dynamics.
“Mitochondrial dynamics plays many different roles, ranging from the most fundamental role of distribution, to integration into signaling pathways and monitoring the status of cells,” Nunnari explained.
LMG trainee Matthew Young, Ph.D., hosted Nunnari’s visit and was impressed by how she used baker’s yeast to characterize components of mitochondrial machineries involving fusion and fission. “Her work has changed the way we think about mitochondria, from static jellybean-like organelles to an intracellular network that is moving, fusing, and dividing,” Young noted.
Mitochondrial dynamics culls the mtDNA herd
Maintaining mtDNA is essential for translating the proper components of the electron transport chain on which human cells rely for ATP production. Mitochondria lack the myriad of DNA damage and mutation avoidance pathways employed by the nucleus and, instead, check the status of the mitochondrial genome using mitochondrial dynamics. Functional mitochondria maintain membrane potential required to drive the electron transport chain, and Nunnari suggested that the membrane potential acts as a gauge to determine the usefulness of mtDNA within the mitochondria.
“This is a quality control pathway where division is constantly questioning the functionality of the mitochondria, while fusion requires membrane potential,” Nunnari postulated. “If mitochondria lose membrane potential, they cannot rejoin and are forever banished from the herd.”
The ability of cells to identify and separate dysfunctional mitochondria is important in neurodegenerative diseases such as Parkinson’s. Two proteins directly linked to Parkinson’s, PINK-1 and Parkin, are important for the targeted destruction of depolarized, or nonfunctional, mitochondria. As Young remarked, the processes involving mitochondrial maintenance and removal appear to be important in understanding human health and disease.
“Mutations in two genes of the human mitochondrial fusion machinery, MFN2 and OPA1, cause tissue-specific neurodegenerative disorders, Charcot-Marie-Tooth 2A and dominant optic atrophy,” Young added.
Picturing mitochondrial proteins in action
Nunnari presented a diverse set of techniques for understanding how mitochondrial fission is regulated. For example, Nunnari used colocalization of mutant variants to show that the dynamin-related protein Dnm1 and its mammalian homologue, Dyn1, functionally interact with the mitochondrial division proteins. To discover the biochemical defects of the mutant variants, Nunnari’s lab solved the three-dimensional structure of Dyn1 and discovered important residues involving the self-assembly of the protein.
In an impressive array of microscopy images, Nunnari suggested a new player in mitochondrial division — the endoplasmic reticulum (ER). The high-resolution images showed that the ER crossed over at positions where mitochondrial division occurs more often. Further experiments identified what Nunnari referred to as ERMES, or ER-mitochondrion encounter structure, where several mitochondrial division proteins and the mtDNA nucleoid colocalized with ER-mediated proteins. The apparent logjam of important division proteins prompted Nunnari to quip, “It’s getting crowded in there, isn’t it?”
Like the rest of the audience, senior researchers were impressed by Nunnari’s ground-breaking research. William Copeland, Ph.D., who leads the NIEHS Mitochondrial DNA Replication Group, acknowledged the significance of Nunnari’s work in the field of mitochondrial biology. “Her current research changes not only how we view mitochondrial structure, but also communication and regulation between cellular components,” he said.