University of California, San Francisco
Yuriy Kirichok, Ph.D.
Yuriy Kirichok, Ph.D.
Jack D. and DeLoris Lange Endowed Chair in Systems Physiology II
Electrical Signaling at the Mitochondrion in Health and Disease
Mitochondria are ubiquitous intracellular organelles responsible for diverse cellular processes including ATP production, intracellular Ca2+ signaling, aging, and programmed cell death. Given the paramount significance of mitochondria in cell physiology, it is not surprising that they have also emerged as key contributors to many pathological conditions, including diabetes, obesity and neurodegenerative diseases. However, development of effective treatment for these disorders has been hampered by our insufficient understanding of the molecular workings of the mitochondrion and how they can contribute to disease.
Electrical potential across the inner mitochondrial membrane (IMM) generated by mitochondrial respiration is fundamental to all physiological and pathophysiological roles of mitochondria, from producing ATP to triggering cell death. Several types of mitochondrial ion channels that mediate fast ion transport across the IMM control this membrane potential and thus directly affect all aspects of mitochondrial function. Ion channels are gated by various intracellular and extracellular cues that act either directly upon the channels or indirectly via associated membrane receptors. Therefore, the ion channels of the IMM are likely to be a major avenue for control of mitochondrial functions by the cell or the entire organism. However, due to the lack of direct functional assays, mitochondrial channels and signaling pathways that affect their activity remain almost completely unexplored.
Recently, we overcame this long-standing technical problem by demonstrating that the patch-clamp technique can be reproducibly applied to the IMM in its entirety. In our lab, we combine this powerful biophysical method with genetics and molecular biology for the comprehensive study of the mitochondrial ion channels and mechanisms of their regulation. Results from this work will uncover the fundamental physiological mechanisms that control mitochondrial functions. In the process, the work will identify mechanisms that can contribute to disease and will suggest effective therapeutic interventions based on manipulating mitochondrial ion channels.Back to Top
1. Electrophysiological and molecular characterization of the mitochondrial Ca2+ uniporter (MCU) and mechanisms of its regulation.
The MCU is a highly selective Ca2+ channel of the inner mitochondrial membrane responsible for mitochondrial Ca2+ accumulation during intracellular Ca2+ signaling. It is important for regulating the rate of mitochondrial ATP production, shaping intracellular Ca2+ signals, and initiating both necrotic and apoptotic cell death. The MCU also has been implicated in regulation of ROS production by mitochondria and thus likely plays an important role in aging and neurodegenerative diseases. Unfortunately molecular identity of this important channel and its mechanisms of regulation remain unknown. We hope to solve this problem and learn more about physiological and pathophysiological roles of the MCU.
2. Comprehensive identification and electrophysiological characterization of mitochondrial ion channels using single-channel and whole-membrane patch clamp recordings from the native inner mitochondrial membrane.
In addition to the MCU, the inner mitochondrial membrane contains proton, potassium and chloride channels as well as a large non-selective pore called the permeability transition pore (PTP). These ion channels, mechanisms of their regulation and their physiological functions remain largely unexplored. We plan to establish the full complement of ion channels located in IMM and prepare basis for their molecular characterization. These results will help us better understand physiological and pathophysiological roles of electrical signaling in mitochondria.Back to Top
Lozovaya N, Melnik S, Tsintsadze T, Grebenyuk S, Kirichok Y, Krishtal O. Protective cap over CA1 synapses: extrasynaptic glutamate does not reach the postsynaptic density. Brain Research 1011: 195-205. (2004)
Kirichok Y, Krapivinsky G, Clapham DE. The mitochondrial Ca2+ uniporter is a highly selective channel. Nature 427: 360-364. (2004)
Kirichok Y, Navarro B, Clapham DE. Whole-cell patch clamp measurements of spermatozoa reveal an alkaline-activated Ca2+ channel. Nature 439: 737-40. (2006)
Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, Krapivinsky L, Kirichok Y, Ramsey IS, Quill TA, Clapham DE. All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. PNAS 104: 1219-23. (2007)
Navarro B, Kirichok Y, Clapham DE. KSper, a pH-sensitive K+ current that controls sperm membrane potential. PNAS 104: 7688-92. (2007)Back to Top