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Thomas Edgar Gunter, Ph.D.

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Office: (585) 275-3129

Fax: (585) 271-2683

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Until recently, the rate of ATP production was thought to be determined by the rate at which ADP and phosphate (Pi) diffuse back to mitochondria. Recent evidence at the cellular and tissue levels suggests control by a novel mechanism, probably functioning through intramitochondrial [Ca2+]. 31P NMR has identified conditions in which [ADP] and [Pi] remain constant while ATP production is increased by a factor of four or more. Clearly, metabolic rate cannot be activated by increased [ADP] and [Pi] if they do not increase, and another mechanism of control is indicated. This additional mechanism is thought to involve intramitochondrial free calcium ([Ca2+]m). Therefore, it is important to determine whether enough Ca2+ can be sequestered by mitochondria under physiological conditions to serve this function of metabolic mediator (1).

Under physiological conditions, cytosolic free calcium ([Ca2+]c) in many tissues remains low (80 to 100 nM) except during pulses or transients of [Ca2+]c. During these pulses, [Ca2+]c can become 1 µM or larger. Even liver, a non excitable tissue, may respond to hormones through a sequence of Ca2+ pulses. A typical hepatocyte response to vasopressin, for example, could be a sequence of 6 or 8 Ca2+ pulses. It is important to determine if mitochondria can sequester enough Ca2+ from such pulses to activate the Ca2+-sensitive steps of the metabolic pathways (1). Calculations based on the kinetics of known mitochondrial Ca2+ transporters suggested that they cannot sequester enough Ca2+(1). However, these kinetics were determined using buffered [Ca2+], not [Ca2+] pulses as under physiological conditions.

We built a device capable of generating Ca2+ pulses like those observed in vivo in many tissues. The [Ca2+] is controlled by a computer-controlled automatic pipetter and measured using fluorescence. We can generate [Ca2+] pulses down to durations of 0.2 - 0.3 sec. over a broad range of [Ca2+]. Using this device, we have discovered a new mechanism of Ca2+ uptake into liver mitochondria, termed the RaM ("rapid mechanism"). Controls show that the RaM mediates rapid net mitochondrial uptake from Ca2+ pulses (2). The RaM briefly displays very high Ca2+ conductivity at the beginning of a pulse; however, the RaM is rapidly closed as the [Ca2+] of the pulse increases. It is quickly "reset" by the fall in [Ca2+] between Ca2+ pulses and therefore functions at the beginning of each pulse. It is sufficiently activated by physiological concentrations of spermine to allow enough Ca2+ to be sequestered from a few pulses to stimulate ATP production. RaM-mediated metabolic signaling shows characteristics of "frequency modulation" (2). The RaM also exists in heart mitochondria; however, its characteristics in heart are quite different from those observed in liver. We believe that this newly discovered mechanism may be the most important component of the system controlling metabolic rate.



BS | Mass Inst Technology

PhD | Univ of Cal Berkeley


Journal Articles

Martinez-Finley EJ, Gavin CE, Aschner M, Gunter TE. "Manganese neurotoxicity and the role of reactive oxygen species." Free radical biology & medicine.. 2013 Sep; 62:65-75. Epub 2013 Feb 08.

Gunter TE, Gerstner B, Gunter KK, Malecki J, Gelein R, Valentine WM, Aschner M, Yule DI. "Manganese transport via the transferrin mechanism." Neurotoxicology.. 2013 Jan; 34:118-27. Epub 2012 Nov 09.

Gunter TE, Gerstner B, Lester T, Wojtovich AP, Malecki J, Swarts SG, Brookes PS, Gavin CE, Gunter KK. "An analysis of the effects of Mn2+ on oxidative phosphorylation in liver, brain, and heart mitochondria using state 3 oxidation rate assays." Toxicology and applied pharmacology.. 2010 Nov 15; 249(1):65-75. Epub 2010 Aug 26.