Gnaiger 2013 MiP2013-Opening
|Gnaiger E (2013) What is mitochondrial physiology – why comparative? Mitochondr Physiol Network 18.08.|
Gnaiger E (2013)
How mitochondria work
10 years after setting the foundations of the Mitochondrial Physiology Society (MiP2003, Schröcken, Austria) our search continues as to what mitochondrial physiology is. Mitochondrial physiology is the study of “how mitochondria work”.
Animal physiology is the study of “how animals work” - says the title of a textbook by Knut Schmidt-Nielsen. Comparative physiology derives its fascination from the diversity of form and function. Organismic variation is studied in diverse environments and in extremes of physiological performance, with explosive activities and high power output in short bursts or endurance over prolonged periods of time with high efficiency. Diversity is nature’s treasure and the subject of comparative physiology. The famous August Krogh principle – Krogh received the Nobel Prize in 1920 - is frequently cited [1,2]: “For a large number of problems there will be some animal of choice or a few such animals on which it can be most conveniently studied.” This principle was first formulated in 1975 by another Nobel laureate who received the Prize in 1953 for the metabolic cycle that carries his name, Sir Hans Krebs [3,4]. This direct link between one of the most famous mitochondrial biochemists and the August Krogh principle that “epitomized the very essence of comparative physiology”  immediately raises the question: Why was comparative mitochondrial physiology not established some 30 to 40 years ago?
• O2k-Network Lab: AT Innsbruck Gnaiger E
Labels: MiParea: Comparative MiP;environmental MiP, mt-Awareness
D. Swarovski Research Lab, Dept. Visceral, Transplant Thoracic Surgery, Medical Univ Innsbruck; and OROBOROS INSTRUMENTS, Innsbruck, Austria;
The world as a laboratory – the Kjell Johansen principle>> Kjell Johansen
In comparative mitochondrial physiology two disciplines converge which were not in immediate conceptual and methodological contact: bioenergetics and comparative physiology. Ladd Prosser divided physiology into cellular physiology, physiology of special groups and comparative physiology, noting for the first category that “at the cellular level all organisms have more in common than in difference” . Accordingly, the physiology and biochemistry of the cell and the bioenergetics of the mitochondrion are focused primarily on unifying principles: the genetic code, the protonmotive force. If there is little variation in the way how mitochondria work, if muscle from horse to mouse simply “builds more mitochondria of the same kind” upon increased energy demand , then diversity is missing as an essential substrate for a comparative science to develop. If the same bricks are used for building libraries and garages, then there is little interest in comparison of bricks. Taking the world as a laboratory  mitochondrial diversity is discovered along with conserved traits: Sir John Walker (Nobel Prize 1997) unravels unity and diversity in Generating the fuel of life (page 8). A paradigm change in mitochondrial physiology comes to light (Kjell Johansen Memorial Session, A1; page 9).
- "In this context I cannot help recalling a discussion I overheard years ago in the Arctic between Larry Irving and some fellow physiologists. The discussion got heated when Larry Irving refused to recognize the white laboratory rat as an animal. He argued that the white rat with food and water ad libitum and a thermostatted cage placed in a regulated light-dark cycle for literally thousands of generations could and should not qualify as an animal. I think Irving won the discussion"  – and Kjell was right (*).
- (*) Martin B, Ji S, Maudsley S, Mattson MP (2010) “Control” laboratory rodents are metabolically morbid: Why it matters. Proc Natl Acad Sci U S A 107: 6127-6133.
Peter Hochachka and his students, colleagues and competitors brought biochemistry into comparative physiology. The influential book by Peter Hochachka and George Somero (1st ed 1973; ) reviews mitochondrial respiration in the global size range from the molecule cytochrome c oxidase to Gaia, and explores exotic animals living in exotic places and adapted to extreme conditions of temperature, hydrogen sulfide concentrations or metabolic shutdown (Session A2). These are excellent examples of the Kjell Johansen principle: “If those species are from Cleveland, choose another problem” (Roy Weber, personal communication; A1-01) or “if you can study an organism in Cleveland, study something else” . The toxic hydrogen sulfide in the extreme habitat of hydrothermal vents was discovered as a substrate for mitochondrial respiration . The pathways were elucidated further in less ‘exotic’ animals, rat liver mitochondria and the intertidal lugworm . Today we discuss mt-respiratory control by H2S in mammalian cells from the extreme environment of the alimentary tract or in the setting of the intensive care unit (Session B1).
Comparative and environmental MiP>> Peter Hochachka
Temperature and hypoxia stand out as prominent chapters in the work of Kjell Johansen and Peter Hochachka. These important topics are largely ignored in mitochondrial bioenergetics, when respiration or ROS production of mitochondria from rat, mouse or human tissues is studied at room temperature or 30 °C (without discussing hypothermia in homeotherms) or at atmospheric oxygen levels (without concern of hyperoxia relative to intracellular pO2 ). Current discussions on the mitochondrial free radical theory of aging (Session C3) rely strongly on comparative studies of nematodes, insects, birds and mammals . Naked mole rats with a 25-30 years maximum life span are compared with mice (3-4 years). The naked mole rat lives in its burrows in Kenya in a natural thermostat with a core body temperature of about 30 °C . Keep this in mind when selecting the temperature in your next experiment on mammalian mitochondria. Experimental temperature comes to mind as a hot MiPchallenge for ectothermic species experiencing a global experiment of climate change (Session A3).
- At the International Summer Course Innsbruck. Calorimetry, respirometry, and biological energetics: from the organelle to the organism (1991) Peter Hochachka presented an “Overview of metabolic suppression in defence against environmental stress: the hypoxia example” - a 4.5 h talk. On the next days, full morning lectures were continued by Steve Hand (Anabolic and catabolic arrest during invertebrate dormancy) and Erich Gnaiger (Muscle and mitochondria at rest and work: Adenylate control and the concept of chemical reaction pressure). During the evening party of the last day, Peter’s enthusiasm caught everybody in an unforgettable slide show: A global perspective of environmental physiology – in the spirit of Kjell Johansen’s “The world as a laboratory”. The marathon lectures received an overwhelmingly positive response by the 55 students. With this in mind, Peter invited me to the World Congress of High Altitude Medicine and Physiology in Cusco (telephone call at 3 am), with the condition to join a pre-conference workshop in Machu Picchu with five participants: In a 4.5 h walk&talk up the Inca trail I talked thermodynamic efficiency  which he enjoyed (photo by EG), whereas Peter expanded on biochemical efficiency in Quechuas on the way down  which was definitely more ‘efficient’. Much later I received a surprising and disturbing letter, where Peter suggested a personal contract to be made: he or me – whoever may survive the other – should organize an event to commemorate the other. For more than a decade I kept this in mind. Outstanding events were organized in Peter’s name. I did not feel prepared to add something living up to his expectations. The present emergence of a new ‘Comparative Mitochondrial Physiology’ is just right to fulfill my contract with Peter.
- 1. Gnaiger E (1993) Efficiency and power strategies under hypoxia. Is low efficiency at high glycolytic ATP production a paradox? In: Surviving hypoxia: Mechanisms of control and adaptation. Hochachka PW, Lutz PL, Sick T, Rosenthal M, Van den Thillart G (eds) CRC Press, Boca Raton, Ann Arbor, London, Tokyo: 77-109.
- 2. Hochachka PW (1993) Adaptability of metabolic efficiencies under chronic hypoxia in man. Ibid: 127-135.
Mitochondrial respiratory control - from unity to diversity
The diversity of mt-respiratory control currently discovered in different species, tissues and cell types is both exciting and disturbing. Disturbing because we have not developed a unifying hypothesis to understand the differential adaptive advantages of the diverse tissue- and species-specific patterns of mitochondrial respiratory control, of variations in ROS production, supercomplex formation and very generally differences in mitochondrial form and function. This presents a challenge to mitochondrial physiology to operate in the intellectual framework of comparative physiology .
One lesson of comparative mitochondrial physiology is straightforward, appears to be simple and important, hence cannot be emphasized enough: If you are interested in humans, study humans and compare. If you want to know about mitochondrial function in heart, study heart and compare.
“Mitochondrial functional diversity will represent a gold mine for mitochondrial physiology, to learn more about mitochondrial function, mitochondrial health and disease” . Three years later this promise is put to the test: Will MiP2013 emerge as a milestone linking comparative concepts with mitochondrial physiology and pathology (Section C), even if important contributions  are missing at a small conference? An energized international mitochondrial network is at work with fission and fusion, excitement, efficiency and high potential to bring comparative mitochondrial physiology to the forefront as a driving force in mitochondrial research and medicine.
- Krogh A (1929) The progress of physiology. Science 70: 200–204.
- Johansen K (1987) The August Krogh lecture: The world as a laboratory. Physiological insights from nature's experiments. In: Advances in physiological research (McLennan H, Ledsome JR, McIntosh CHS, Jones DR, eds). Plenum Publishing Corporation: 377-396.
- Krebs HA (1975) The August Krogh Principle: "For many problems there is an animal on which it can be most conveniently studied". J Exp Zool 194: 221-226.
- Joergensen CB (2001) August Krogh and Claude Bernard on basic principles in experimental physiology. BioScience 51: 59-61.
- Prosser CL, Brown FA 1961. Comparative animal physiology. Saunders. 2nd ed.
- Weibel ER, Taylor CR, Hoppeler H (1991) The concept of symmorphosis: a testable hypothesis of structure-function relationship. Proc Natl Acad Sci U S A 88: 10357-10361.
- Hochachka PW, Somero GN (2002) Biochemical adaptation: mechanism and process in physiological evolution. Oxford Univ Press, New York: 466 pp.
- Somero G, Suarez RK (2005) Peter Hochachka: Adventures in biochemical adaptation. Annu Rev Physiol 67: 25-37.
- Hildebrandt TM, Grieshaber MK (2008) Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J 275: 3352-3356.
- Gnaiger E, Méndez G, Hand SC (2000) High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. Proc Natl Acad Sci U S A 97: 11080-11085.
- Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123: 951-957.
- Somero GN (2000) Unity in diversity: a perspective on the methods, contributions, and future of comparative physiology. Annu Rev Physiol 62: 927-937.
- Gnaiger E (2010) Seven years Mitochondrial Physiology Society and a welcome to MiP2010: Bioblasts – the aliens with permanent residence in our cells. Mitochondr Physiol Network 15.06: 25-28.
- Müller M, Mentel M, van Hellemond JJ, Henze K, Woehle C, Gould SB, Yu RY, van der Giezen M, Tielens AG, Martin WF (2012) Biochemistry and evolution of anaerobic energy metabolism in eukaryotes. Microbiol Mol Biol Rev 76: 444-495.