Mitochondria perform fundamental functions in eukaryolic cells, including ATP production via respiration and cellular ion and phospholipid homeostasis. They also serve as platforms to integrate signaling pathways such as cell death and innate immunity. Mitochondrial functions are tightly linked to mitochondrial form, established through separate, but somehow coordinated machines that control dynamics, positioning, motility and mitochondrial DNA (mtDNA) transmission. The endoplasmic reticulum (ER) has emerged as an integral and pervasive player in the regulation of mitochondrial form and function. The ER exerts its role through contacts with mitochondria, which our data indicate create specialized microdomains that recruit and/or modulate resident effectors to control and integrate mitochondrial status with other organelles and signaling pathways. In this MERIT award, we are exploring the fundamental properties and functions of membrane contact sites (MCS), with a particular emphasis on ER-mitochondria contact sites using budding yeast, where they are the best characterized. We have shown that one MCS, ERM ES, serves as a systems regulator to create a cellular pathway for the transmission of mtDNA and that this function of ER-mitochondria contacts is fundamentally conserved in human cells. We will extend our findings to explore the molecular basis of the action of the ERM ES complex in mtDNA transmission. We also discovered a family of conserved contact site proteins that serve to transport sterols and regulate Ca2+ homeostasis at ER-plasma membrane, ER-vacuole/lysosome and ER-mitochondria contacts in yeast and human cells. We will utilize high resolution yeast genetics to discover the unknown but fundamental role of sterol transport between the ER and mitochondria. New information in this area of cell biology will provide insight into the general architecture and roles of ER MCSs and their regulation of mitochondrial function and cellular homeostasis to more accurately reveal role of mitochondria in human diseases.
|Friedman, Jonathan R; Kannan, Muthukumar; Toulmay, Alexandre et al. (2018) Lipid Homeostasis Is Maintained by Dual Targeting of the Mitochondrial PE Biosynthesis Enzyme to the ER. Dev Cell 44:261-270.e6|
|Horenkamp, Florian A; Valverde, Diana P; Nunnari, Jodi et al. (2018) Molecular basis for sterol transport by StART-like lipid transfer domains. EMBO J 37:|
|Murley, Andrew; Yamada, Justin; Niles, Bradley J et al. (2017) Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling. J Cell Biol 216:2679-2689|
|Murley, Andrew; Nunnari, Jodi (2016) The Emerging Network of Mitochondria-Organelle Contacts. Mol Cell 61:648-653|
|Lewis, Samantha C; Uchiyama, Lauren F; Nunnari, Jodi (2016) ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353:aaf5549|
|Murley, Andrew; Sarsam, Reta D; Toulmay, Alexandre et al. (2015) Ltc1 is an ER-localized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts. J Cell Biol 209:539-48|