From Bioblasts to Mitochondria: Ever Expanding Roles of Mitochondria in Cell Physiology

Historical PersPective Science’s fascination with mitochondria spans more than 120 years, and whenever I find time for a respite from grant deadlines and other obligations, I enjoy following a trail of references back through the ages. I recall a few years ago finding a treasure after a quick search of our library’s online catalog – an 1890 edition of “Die elementarorganismen und ihre beziehungen zu den zellen” by Richard Altmann (Altmann 1890). This tome is recognized as a transformative early histological description of mitochondria, or in his terminology, “bioblasts” (life germs), which he believed were autonomous elementary organisms responsible for metabolic and genetic functions. Even more surprisingly, I could simply request to have the volume delivered to me from the reserves as an ordinary loan. Paging through the yellowed leaves, I was amazed by the accuracy and beauty of the drawings (see Figure 1), and I was compelled to spend half a day scanning the figures into my computer (of course, I now find that a pdf is available on Google Books http://books.google. com/books? id=hLhUAAAAMAAJ&oe=U TF-8). Characterizing them as the “living beings” of the cell, Altmann was clearly captivated by mitochondria, although his enthusiastic spirit was dampened by scathing criticism from his peers, including Professor F.P. Mall, who at one time headed the Anatomy Department of Johns Hopkins and was working in Leipzig at the time (Cowdry, 1953). Apparently, Altmann did not fare well under the onslaught and became a recluse in his own office, earning the nickname “the ghost” (Cowdry, 1953), only to pass away in 1900. Nevertheless, his notion that mitochondria resembled bacteria, and had metabolic and genetic functions were, in the end, not far from the truth; borne out by the theory of endosymbiosis (Wallin, 1927; Margulis, 1970), the role of mitochondria in genetic (albeit maternal) inheritance (Payne, 1909; Schapira, 2006) and energy metabolism (Kingsbury, 1912; Chance and Williams, 1955; Mitchell, 1961; Lehninger and Wadkins, 1962; Krebs, 1970; Nicholls and Ferguson, 2002). The seeds of several areas of interest important to modern mitochondrial biologists can also be found in the literature of the early 20th century. For example, an interesting review of the state-of-the-art of mitochondrial research in 1918 by Cowdry (Cowdry, 1918) (available at http://www.archive.org/ download/carnegieinstitut2711918carn/ carnegieinstitut2711918carn.pdf) discusses fragmentation of mitochondria at the onset of degenerative tissue injury, the fission and fusion of mitochondria in living cells (see also the elegant work of Lewis and Lewis, 1915), the role of mitochondria in tissue regeneration, inheritance, metabolism, and respiration, among other possible functions. Also around this time, the close correlation between oxygen consumption and muscle work was being investigated (Evans and Matsuoka, 1915). Somewhat later, the ability of mitochondria to avidly take up Ca2+ was noted (see historical view in Carafoli, 2003) and this important ability has emerged as a crucial regulator of both intracellular Ca2+ balance and energy supply and demand. Of course, this process, taken to the extreme, can also trigger a mitochondrial permeability transition and cell death. In launching a new journal called “Frontiers in Mitochondrial Physiology”, it is worth considering that each major new idea involving mitochondria has at one time or another been roundly criticized. The preeminent case in point was the radical chemiosmotic hypothesis of Mitchell. Anyone who reads the history of this period (a fascinating account is given in Prebble and Weber, 2003) will recognize that new ideas in mitochondrial biology (as in other disciplines) have a tough time breaking down entrenched dogma. Who today would have the wherewithal or persistence to establish one’s own institute to prove a point? Indeed, the limitations of the contemporary technology at the time made proof of the elegant idea of chemiosmosis difficult to come by initially. Nevertheless, as technology progressed, including membrane potential measurements and improved ion detection methods, the case was made stronger, but it still took more than a decade to become widely accepted. Indeed, new technologies are emerging at a rapid pace and are providing new insights into the regulation of mitochondrial function and the role of mitochondria in cell physiology. Most importantly, new approaches are helping to resolve some longstanding questions. A major goal of this journal should be to keep the history of progress in mitochondrial research in mind so as not to prematurely discard novel ideas, and especially to avoid ad hominem attacks while promoting constructive criticism (no one should end up like Altmann! ). In describing the tension between maintaining a healthy skepticism and being open to new ideas, Carl Sagan wrote that “at the heart of science is an essential balance between two seemingly contradictory attitudes – an openness to new ideas, no matter how bizarre or counterintuitive, and the most ruthlessly skeptical scrutiny of all ideas, old and new. This is how deep truths are winnowed from deep nonsense. The collective enterprise of creative thinking and skeptical thinking, working together, keep the field on track. ” I am sure we are all familiar with the occasional “ruthlessly skeptical” reviewer (or have assumed the role at one time or another), but let this quotation serve as a reminder to never abandon our sense of openness to new ideas.