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Recent Developments in Mitochondrial Medicine (Part 1) 4open 2021, 4,2 Ó V. Weissig & M. Edeas, Published by EDP Sciences, 2021 https://doi.org/10.1051/fopen/2021002 Available online at: www.4open-sciences.org REVIEW ARTICLE Recent developments in mitochondrial medicine (Part 1) Volkmar Weissig1,* and Marvin Edeas2,3 1 Midwestern University, College of Pharmacy, Department of Pharmaceutical Sciences, 19555 N. 59th Avenue, Glendale, AZ 85308, USA 2 Université de Paris, INSERM U1016, Institut Cochin, CNRS UMR8104, Faculté de médecine Cochin-Port Royal, 75014 Paris, France 3 Laboratory of Excellence GR-Ex, 75015 Paris, France Received 15 February 2021, Accepted 15 April 2021 Abstract – Research into elucidating structure and function of mitochondria has been quite steady between the time of discovery during the end of the 19th century until towards the late 1980’s. During the 1990s there was talk about a “comeback” of this organelle reflecting a widely revitalized interest into mitochondrial research which was based on two major discoveries made during that time. The first was the etiological association between human diseases and mitochondrial DNA mutations, while the second revealed the crucial function of mitochondria during apoptosis. The March 5th, 1999 issue of Science even featured a textbook image of a mitochondrion on its front cover and was entirely dedicated to this organelle. Whilst the term “comeback” might have been appropriate to describe the general excitement surrounding the new mitochondrial discoveries made during the 1990s, a term for describing the progress made in mitochondrial research during the last two decades is difficult to find. Between 2000 and 2020 the number of publications on mitochondria has skyrock- eted. It is now widely accepted that there hardly exists any human disease for which either the etiology or pathogenesis does not seem to be associated with mitochondrial malfunction. In this review we will discuss and follow several lines of mitochondrial research from their early beginnings up to the present. We hope to be able to convince the reader of what we expressed about a decade ago, that the future of medicine will come through mitochondria. Keywords: Biochemistry, Cells, DQAsome, Lipoplexe, Heteroplasmy, miRNA, Mitochondrial medicine, Mitochondrial diseases, Mitochondrial DNA, Mitochondrial dysfunction, Mitochondrial research, Mitochondrion, Mitochondrium, mitomiRs, mtDNA, Organelle, Physiology, PNA, Research, Science Introduction Mitochondria contain their own DNA and as shown by Doug Wallace and his group in 1980 [3] are maternally All human cells, except erythrocytes, harbor mitochon- inherited. A recently claimed biparental inheritance of dria in the form of a tubular network constantly undergoing mitochondria in humans [4] however has triggered some fission and fusion. Known as the “powerhouse of the cell ”, contentious discussions [5, 6]. Based on correlating mito- they are at the juncture of energy-producing pathways, as chondrial DNA (mtDNA) variations between populations the “cell’sarsenal” they play a decisive role in programmed from around the world Wallace was able to reconstruct cell death (apoptosis). In addition, mitochondria are origin and migration patterns of women in ancient times, involved in a multitude of anabolic, catabolic, and signaling which gave rise to the speculation about a “Mitochondrial pathways. Eve” the most recent female from whom all humans might According to the endosymbiotic theory mitochondria have descended. are descended from once free-living bacteria which were Mitochondrial DNA encodes for 13 polypeptides essen- engulfed by prokaryotic cells. This today generally accepted tial for energy production; all other mitochondrial proteins evolutionary theory was proposed for the first time in 1966 encoded by nuclear DNA are imported from the cytoplasm. by Lynn (Sagan) Margulis who had, as she remembers [1], The amount of mitochondrial mass per cell organized as a to submit her corresponding manuscript to about 15 differ- sub-micro- to nano-structured tubular network extending ent journals before it was accepted by the Journal of three-dimensionally around the nucleus and throughout Theoretical Biology [2]. the cytoplasm depends on the energy demands of the cell. Organs with the highest energy consumption are the brain, *Corresponding author: [email protected] skeletal muscle, the kidney cortex, liver, heart and the This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 V. Weissig and M. Edeas: 4open 2021, 4,2 visual system. Though mitochondrial malfunction as the be visible under the light microscope. Light microscopy cause of human disease was described for the first time in however does not allow for a more detailed structural 1962 [7], the genetic basis for mitochondrial diseases analysis of mitochondria. remained elusive until 1988 [8]. Subsequent research over Their major structural features, which are an outer the last three decades has revealed that there is hardly membrane and a highly convoluted inner membrane, were any human disease the etiology or pathogenesis of which made visible for the first time during the early 1950’swhen is not associated with mitochondrial malfunction, a realiza- George Emil Palade (1912–2008, Nobel Prize Physiology tion leading us [Marvin Edeas and Volkmar Weissig (ME & 1974) investigated the organelle under the electron micro- VW)] to conclude that “the future of medicine will come scope [16, 17]. Based on Palade’s work a model for the inner through mitochondria” [9]. structure of mitochondria was developed which dominated In this review, written for “non-mitochondriologists”,we the literature for up to 50 years (Fig. 1A). According to this outline about 170 years of mitochondrial research whilst model, mitochondria have two aqueous sub compartments, emphasizing the major groundbreaking discoveries and the intermembrane space (IMS) between the outer and the developments made since the beginning of the new century. inner membrane and the so-called mitochondrial matrix. Because we (ME & VW) have been hosting in Berlin Here it should be noted that although the term “aqueous (Germany) the Annual World Conference on Targeting sub compartments” is still widely used, it is misleading. Mitochondria since 2010 (the 12th edition will take place Due to the presence of between 1100 and 1400 [18] distinct in October 2021), we are fortunate to know on a personal proteins, the mitochondrial matrix “constitutes a biochemi- level many of the major investigators who are pushing mito- cal reaction environment with a highly complex structure” chondrial research forward. In this review, we highlight [19]. The viscosity of the mitochondrial matrix solvent has their contributions to the field of mitochondrial medicine. been determined to be between 2.69 and 3.32 cP, which can, under a variety of physiological and pathological conditions increase up to 30-fold [19]. For comparison, the From “thread-like granules” to “cristae viscosity of water is about 1 cP. junctions” In Palade’s model no barrier exists between the space inside the cristae and the IMS. This model became obsolete Studies using light microscopy on cells during the towards the end of the 1990’s when Perkins and Frey second half of the 19th century uncovered the existence of investigated mitochondrial morphology by electron micro- small subcellular granules [10] which in shape and size were scope tomography [20, 21] and discovered junctions at the similar to bacteria as observed by Richard Altmann (1852– neck of cristae (Fig. 1B). Due to their narrow diameter of 1900) who named them “bioblasts” in 1890 [10, 11]. Based on about 12–40 nm, these junctions were proposed to impede the Greek, eight years later, Carl Benda (1857–1932) coined the flow of proteins and metabolites towards and away from the term “mitochondria” in 1898 [12], with “mitos” meaning cristae thereby creating an aqueous compartment distinct thread and “chondrion” meaning grain. Noteworthy, from the IMS and also separated from the mitochondrial although obviously already recognized at the end of the matrix. 19th century, the thread-like morphology of mitochondria Studies conducted during the last decade, [22] have only became fully appreciated at the beginning of the 21st revealed major protein complexes which control the century when it was revealed that the maintenance of the formation of cristae and their junctions, among them optic tubular (thread-like) network characteristic of mitochon- atrophy 1 protein (OPA1) and the mitochondrial contact dria is critical for human health [13–15]. The appearance site and cristae organization system (MICOS) (Fig. 1B). of mitochondria as individual objects usually indicates a Controlling cristae junctions is crucial for mitochondrial severely damaged mitochondrial network as present in function. In the mid-1960s, Charles Hackenbrock reported unhealthy, dying cells or as an artifact of sample processing that ultrastructural changes of mitochondrial cristae were for microscopic images. Unfortunately, the depiction of associated with metabolic changes [23–25]. In 2002, Stanley mitochondria in text books as single bean-like shaped Korsmeyer and co-workers showed that cristae remodeling bodies seems to be still very common. is an essential step during a highly complex pathway lead- By 1930, most cytologists had
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