Van Andel Research Institute

Mechanisms of Mutant Mitochondrial Genome Modulation - Project Summary/abstract Ever Since Forming a Symbiotic Relationship With the Eukaryotic Host 2 Billion Years Ago, Mitochondria Have Become Integral Components of the Cellular Network. Thanks to the Resurgence of Interest in Mitochondria, There Is a Greater Appreciation for the Wide Variety of Cellular and Physiological Functions for These Organelles Beyond Their Role in Energy Generation. Despite This Renewed Interest, However, Research Into the Mitochondrial Genome (MTDNA) Has Lagged. Multiple Factors Likely Contribute to This Underappreciation for Mtdna, Including Its Diminutive Size and Small Genetic Content, the Difficulty of Genetically Manipulating It in Metazoans, and Its ‘messy’ Genetics, Which Stands in Stark Contrast to the Simple and Elegant Mendelian Genetics of the Nuclear Genome. Consequently, Fundamental Questions Pertaining to Mtdna Biology Remain Unaddressed. It Is a Mistake, However, to View Mtdna as Simple and Inconsequential Vestiges of Mitochondria’s Ancestral Past. Devastating Diseases Caused by Mtdna Mutations Serve as Important Reminders of Its Functional Relevance. the Overarching Goal of Research in My Lab Over the Coming Five Years Is to Study Mtdna Genetics, and Mtdna Biology More Broadly. Replication of Mtdna Is Not Confined to the Cell Cycle and Can Occur Continuously Throughout the Life of the Cells. Consequently, New Mutations Can Arise Frequently, Contributing to a State of Heteroplasmy, in Which Two or More Sequence Variants of Mtdna Coexist. Because Cells Are Polyploid for Mtdna, Containing Hundreds to Thousands of Copies, Mutations Are Scored as the Percentage of Mtdna Copies That Are Mutant (i.e. Heteroplasmy Levels). Even Highly Deleterious Mtdna Mutations Are Benign at Low Heteroplasmy Levels. However, They Become Pathogenic When Their Levels Rise Beyond a Critical Threshold and There Are Insufficient Copies of the Normal Mtdna to Support Cellular Function. the Cellular and Molecular Mechanisms That Impact Heteroplasmy Levels Are Poorly Understood. Consequently, It Is Difficult to Predict Who Will Inherit or Develop Mtdna-associated Diseases. the First Major Goal of My Lab Is to Identify the Cellular and Molecular Mechanisms That Modulate Heteroplasmy Dynamics. We Have Adapted C. Elegans as a Model System of Choice to Study These Mechanisms. C. Elegans Allows Us to Track Heteroplasmy Levels Across Individuals and Generations With Unprecedented Feasibility. the Ability of Mtdna Mutants to Rise in Heteroplasmy Levels Beyond the Critical Threshold Are Mutant- Specific. However, the Mechanistic Basis for This Specificity Is Not Well Understood. Consequently, the Second Major Goal of My Lab Is to Utilize a Diverse Panel of Mutations to Explain the Differences in Their Heteroplasmy Levels. Taken Together, Our Research Program Tackles Long-standing But Fundamental Questions in the Field of Mitochondrial Genetics. in the Process, We Will Also Gain Insights Into Broader Aspects of Mtdna Biology Such as Its Replication and How Cells Count Mtdna Copies.