Why Do Plants Have Mitochondria

Med Sci Monit. 2015; 21: 2073–2078.

Mitochondria, Chloroplasts in Animal and Plant Cells: Significance of Conformational Matching

Received 2015 May 25; Accustomed 2015 Jun 26.

Abstract

Many commonalities between chloroplasts and mitochondria exist, thereby suggesting a common origin via a bacterial ancestor capable of enhanced ATP-dependent energy product functionally linked to cellular respiration and photosynthesis. Appropriately, the molecular development/retention of the catalytic Q_o quinol oxidation site of cytochrome b complexes as the tetrapeptide PEWY sequence functionally underlies the common retention of a chemiosmotic proton slope mechanism for ATP synthesis in cellular respiration and photosynthesis. Furthermore, the dual regulatory targeting of mitochondrial and chloroplast gene expression by mitochondrial transcription termination factor (MTERF) proteins to promote optimal energy production and oxygen consumption further advances these evolutionary contentions. As a functional effect of enhanced oxygen utilization and production, significant levels of reactive oxygen species (ROS) may be generated within mitochondria and chloroplasts, which may effectively compromise cellular energy production following prolonged stress/inflammationary conditions. Interestingly, both types of organelles have been identified in selected animal cells, most notably specialized digestive cells lining the gut of several species of Sacoglossan ocean slugs. Termed kleptoplasty or kleptoplastic endosymbiosis, functional chloroplasts from algal food sources are internalized and stored inside digestive cells to provide the host with dual energy sources derived from mitochondrial and photosynthetic processes. Recently, the observation of internalized algae within embryonic tissues of the spotted salamander strongly suggest that developmental processes within a vertebrate organism may require photosynthetic endosymbiosis as an internal regulator. The dual presence of mitochondria and functional chloroplasts within specialized animal cells indicates a high degree of biochemical identity, stereoselectivity, and conformational matching that are the likely keys to their functional presence and essential endosymbiotic activities for over 2.5 billion years.

MeSH Keywords: Chloroplasts, Kleptoplasty, Mitochondria, MTERF, PEWY, Reactive Oxygen Species, Stereospecificity

Background

Mitochondria and chloroplasts represent endosymbiont models of complex organelle development driven by evolutionary modification of permanently enslaved primordial bacteria[1–4]. Over diverse eukaryotic phyla mitochondria and chloroplasts either solitary or together provide a concerted distension of cellular energy production via shared biochemical pathways. Cellular dysregulation of these two distinct organelles may generate potentially dangerous reactive oxygen species (ROS) due to compromised complex bioenergetics energy production, systemic oxidative stress and compounded pro-inflammatory processes. Importantly, genetically- or biochemically-mediated failure of mitochondrial function in human populations represents a potentially dire gene in the etiology of major affliction states that include Type II diabetes, atherosclerosis, rheumatoid arthritis, Alzheimer's Disease, and cancer progression [5–21]. In sum, these compelling mechanistic and clinical data propose that the extent of mitochondrial/chloroplast regulatory signaling may vary over the lifetime of the eukaryotic prison cell according to physiological demand and bioenergetics requirements[22,23].

Interestingly, a tumor prison cell may exist viewed as a phenotypic reversion to the last common eukaryotic ancestor of the host cell, i.eastward., a facultative anaerobic microbe with unlimited replication potential [24]. For example, anaerobic mitochondria in gill cilia of Yard. edulis have evolved to utilize the phenotype of a facultative anaerobe, demonstrating that this primitive blazon of respiration has been evolutionarily conserved [25,26]. Accordingly, anaerobically operation mitochondria may correspond a re-emergence or evolutionary retrofit of primordial metabolic processes.

Information technology has become recently credible that mitochondria take detached microenvironments composed of complex intracellular membrane structures with distinct functional identities adamant past segregated biochemical pathways [27] (Figure i). Given the shared chemical messengers between the 2 and interrelationships betwixt the common energy processes information technology is not surprising that additional commonalities are emerging. Furthermore, information technology is no surprise that mitochondria are nowadays in both plants and animals, implying major shared regulatory, bioenergetic, and chemical substrate pathways. Commonalities of energy processing in both plants and animals accept become even stronger by the finding that chloroplast tin be plant in animal cells. The discovery of kleptoplasty, a functional chloroplast in cells of a non-photosynthetic host [28] is a remarkable phenomenon [28–31]. Information technology is too found in metazoans, i.e., the sacoglossan sea slug. Of equal importance is the longevity of functional kleptoplasts in the host, suggesting again the mutual significance of bidirectional communication and the many commonalities in molecules exist so that this phenomenon can take identify and work. These sea slugs extract and contain functional chloroplasts from Ulvophyceae into their gut cells [32], allowing their derived "food" to exist gained for months. The dependence on specific algae strongly suggests common bidirectional communication is responsible for these phenomena.

An external file that holds a picture, illustration, etc. Object name is medscimonit-21-2073-g001.jpg

The prokaryotic cell is characterized past a general lack of highly structured intracellular organelles but displays intracellular regions of functionality with some membrane enhancements, east.k., mesosome. Nosotros surmise that with fourth dimension this relatively unproblematic structure became more elaborate, calculation membrane surface surface area to perform work, enhancing a major function like respiration. In all probability the stimulus was solar energy, causing the photolysis of water. This cell was driven in this direction because information technology provided a new coping strategy for, counter-intuitively, Dna advocacy. This evolving cellular architecture could not survive on its own given the presence of by products it produced, e.yard., ROS, which are basically toxic to unprotected intracellular components, notably Dna. This evolutionary self protection machinery was farther avant-garde when oxygen levels increased as a result of photosynthesis. In all probability the cellular oxygen toxicity issue was partly solved by having a "bacterium" develop in a "bacterium", becoming a eukaryotic cell, which could harvest specific bond energy. This also aided in ROS protection with a more structured and protected environment for this new intracellular relationship to evolve, having a plentiful energy supply for novel Deoxyribonucleic acid expression. Accordingly, a major free radical and complimentary radical creator was effectively removed via chloroplasts, which originated in a like style as mitochondria. Thus, information technology is not surprising to find both types of "bacteria" in the same prison cell and others where but i is nowadays. Furthermore, given this close evolvement, enslavement was not an upshot in this circumstance considering each "cell" used the same or similar chemical messengers, stabilizing what appears to be a precarious relationship. Indeed, bidirectional advice served every bit the process for eukaryotic cellular communication/cooperation, which immune for metazoan evolution. Interestingly, metazoan evolution is even so highly dependent on the intracellular communication with its endogenous bacterial components from which it evolved, e.g., intracellular and extracellular (gut microbiome). The vulnerability expresses itself in "mitochondrial dysfunction" in that it can be so complicated and diverse depending on the tissue region affected. We farther surmise that hypoxia plays a major role in triggering mitochondrial dysfunction since this entire relationship depends on a continuously ongoing free energy processing organisation[2,21]. Briefly, the evolutionary advancement of eukaryotic cells requires this homeostatic energy balance to maintain its multicomponent and faceted existence. Whatsoever deviation from the thermodynamically stabilized life form creates a pathology wherever it occurs. This procedure may too correspond the deleterious mechanisms that may be associated with crumbling.

The ability of a chloroplast to part as a symbiotic bioenergetic organelle within the intracellular milieu of a representative invertebrate, i.e., the Sacoglossan ocean slug, was previously identified as a unique phenomenon unlikely to occur in vertebrates [28–32]. Recently, the ascertainment of internalized algae inside embryonic tissues of the spotted salamander strongly suggest that developmental processes within a vertebrate organism may require photosynthetic endosymbiosis every bit an internal regulator [33]. Accordingly, it appears that dark-green algae and spotted salamander embryos take an intimate endosymbiotic relationship and algae are able to invade the embryonic tissues and cells of the salamander and eventually degrade as the larvae develop over time [33]. Although endosymbiotic algal cells go through degradation, the cells can also encyst on the inner capsule wall which is detected through 18s rDNA distension in the reproductive tracts of the adult salamanders, thereby assuasive for the transfer of genes from i generation to the next [33]. Due to the dumbo accumulation of algae within the embryo, a distinct greenish colour is exhibited which leads to beneficial effects for the embryo. Requisite physiological effects include lowering embryonic bloodshed, larger embryo size, and earlier hatching times. It is all the same unclear if the algae and the embryo take a true bidirectional symbiotic relationship because there is evidence that the algae take no increase in oxygen levels, only they may do good from the embryos when their nitrogenous waste is released. In any effect, this phenomenon defines a distinctive relationship betwixt developmental processes in a defined vertebrate organism and eukaryotic algae.

A conscientious examination of the biomedical literature has yielded many examples of existential commonalities between mitochondria and chloroplasts, which include gratis living leaner [34]. Formally known as the PEWY motif in mitochondrial complexes, cyt b displays 4 tetrapeptide residues (PDWY, PPWF, PVWY and PEWY) employed in catalytic reactions, which is now identified equally the Q_o motif. PEWY, which is present in chloroplasts and mitochondria, and PDWY which is present in Gram-positive bacteria both associate with the redox potential of quinone species [34]. These information propose that when electron transfer occurs from a depression-high potential throughout evolution that the cyt bc1 complex with PEWY beingness the Q_o motif will function all-time with a high potential and ubiquinone as its substrate [34]. For PDWY as the cyt b complex, a low potential and menaquinone volition function the best. In sum, the molecular evolution/retention of the catalytic Q_o quinol oxidation site of cytochrome b complexes, functionally underlies the common retention of a chemiosmotic proton gradient machinery for ATP synthesis in cellular respiration and photosynthesis.

The relationship between photosynthesis and respiration can vary, thereby demonstrating their dynamic nature. For case, when tomato fruit ripen, their chloroplasts will alter into photosynthetically inactive chromoplasts that can produce ATP through a respiration process known as chromorespiration [35]. Oxygen consumption through chromorespiration tin exist stimulated by NADH and NADPH, and is also sensitive to the plastidial terminal oxidase inhibitor octyl gallate. Isolated chromoplasts are besides sensitive to multiple molecules such every bit the cytochrome b _half-dozen f complex inhibitor 2,5-dibromo-3-methyl-6-isoproply-p-benzoquinone [35]. Cytochrome f was identified in the chromoplast as was cytochrome c6 and their expression increases in ripened tomatoes suggesting that they may exist acting as electron acceptors for the cytochrome b _six f complex. During ripening, mitochondrial numbers significantly decrease in the fruit tissue [35]. In order to compensate for this potent subtract, the number of chromoplasts will functionally increase during the later stages of ripening, thereby demonstrating critical modification of energy processing.

Importantly, plants crave imported oxygen to carry out most of their biochemical reactions such as respiration even though they lack the ability to distribute oxygen to the cells [36]. To compensate for the lack of this distribution mechanism, plants oftentimes display steep oxygen gradients that may exist impaired due to environmental distress [36]. Thus, plants require different physiological responses to manage the variations of oxygen levels available to them and display metabolic adaptations in energy requirements. Equally a key example, physiological need is coupled to activation of the cellular glycolytic pathway to generate ATP production when oxidative phosphorylation is compromised [27]. Cellular oxygen levels have been demonstrated to regulate the expression of Grouping-Vii ethylene response factors (ERFs), a family of transcription factors involved in the regulation of hypoxia-inducible genes that include HRE1 and HRE2 [36]. Furthermore, the functional integrity of mitochondria and chloroplasts are critically linked to cellular oxygen requirements, every bit regulated past the N-cease rule signaling pathway due to the impacted loss. The N-end rule signaling pathway represents a cellular response mechanism that requires ubiquitin ligation linked to proteasomal deposition via covalent modification of Due north-terminal amino acids [36].

Finally, the assortment of complex control machinery past which organellar factor expression (OGE) promotes respiration, photosynthesis and plant evolution is actively under investigation [37]. Presently, several required components take been identified that accept been functionally associated with OGE processes. Nucleus-encoded proteins have important roles in OGE by promoting various required functions such equally splicing, transcription, RNA processing and regulation of translational processes. Normative OGE is regulated past the family unit of mitochondrial transcription termination factors (mTERF). Mammalian mTERFS were originally proposed to specifically cease transcription, but further biochemical and molecular studies indicate that three out of the four mTERFS possess of import regulatory activities necessary for ribosomal biogenesis and antisense transcription termination. Approximately 30 members of the mTERF family have been identified throughout plant evolution, just all the same little is known nigh how photosynthetic organisms are using mTERFs and OGE [28]. In sum, the dual regulatory targeting of mitochondrial and chloroplast gene expression by mTERF proteins to promote optimal energy production and oxygen consumption further advances the evolutionary importance of OGE processes.

Conclusions

It is now established that the same set of functional genes are encoded in both the plastid and mitochondrial genomes, which express the aforementioned conserved proteins in the electron ship chain [38]. Thus, information technology is strongly implied that OGE processes are critically linked to shared stereo-selective biochemical pathways. Maier and colleagues refer to this as an example of parallel and convergent evolution. The ongoing processes underlying biologically meaningful evolutionary modification of the organellar genome can be partly attributed to regulatory stability of intracellular redox processes. As such, a hypothesis of evolutionary modification of intracellular redox regulation predicts that at that place is a specific location for the plastids and mitochondria genes that encode for bioenergetics membrane proteins that are functionally related to respiration or photosynthesis [38]. The dual evolution of the plastid and mitochondria genomes will effectively drive the retention of functionally similar sets of ribosomal protein genes which are functionally required for proper ribosomal assembly.

It has been recently proposed that archaebacterium and eubacterium precursors led to the origin of eukaryotes [39,40]. Conversely, mitochondria arose from an alpha-proteobacterium and a eukaryote [twoscore,41]. Plastids arose in a similar mode merely from cyanobacterium and a eukaryote [40]. Hence the eukaryotic prison cell was "developed". The developmental primacy of photosynthesis was probably due to abundant sunlight and coincident appearance of requisite photovoltaic chemic processes. Furthermore, the byproducts of these processes, i.eastward., glucose and oxygen, introduced a major alter in the biosphere with the associated evolutionary evolution of complex cellular respiratory processes and with major potential issues involving oxygen toxicity. In light of these changes, both photosynthetic and respiratory processes were driven by the potential for bacteria to further enhance the intracellular membrane microdomains segregated according to functional physiological criteria.

Accordingly, the respiratory "bacterium" evolved and remained in place because of its existential brokerage of molecular oxygen and the utilize of glucose as an initial fuel source in the bioenergetics of ATP production. In this regard, photosynthetic priming events promoted evolutionary acceleration of intracellular membrane differentiation, selective for plastid-like structures. This major contention is supported past the observation that many organelles can exist found in both constitute and animal cells and that their molecular biology/bioenergetics share basic chemical processes.

The dual expression of mitochondria and functional chloroplasts within specialized fauna cells indicates a high degree of biochemical identity, stereoselectivity, and conformational matching that are the likely keys to their functional presence and essential endosymbiotic activities for over two.five billion years [3,42–44]. Thus, conformational matching imposes a high degree of rigidity on the systems, allowing for their retention in evolution. Another component of the conformational matching hypothesis is that this phenomenon as well occurs via a chemical messenger and its receptor with the added fact that both must be expressed simultaneously and appropriately on the right target [3,42–44]. Therefore, all the conformational dependent substrates and enzymes impose a rigidity on change in general, which does not favor change. Withal, change tin can and does occur because slight changes may be tolerated, giving ascent to modified systems, e. g., the catecholamine pathway.

Footnotes

Conflict of interests

The authors declare no disharmonize of interests.

Source of support: The report was, in part, funded by MitoGenetics, LLC (Sioux Falls, S Dakota)

References

1. Stefano GB, Kream RM. Psychiatric disorders involving mitochondrial processes. Psychology Observer. 2015;1:i–six. [Google Scholar]

2. Stefano GB, Mantione KJ, Casares FM, Kream RM. Anaerobically functioning mitochondria: Evolutionary perspective on modulation of free energy metabolism in Mytilus edulis. Invertebrate Survival Journal. 2015;12:22–28. [Google Scholar]

3. Snyder C, Stefano GB. Mitochondria and chloroplasts shared in animal and found tissues: significance of communication. Med Sci Monit. 2015;21:1507–xi. [PMC free article] [PubMed] [Google Scholar]

4. Mantione KJ, Kream RM, Stefano GB. Variations in disquisitional morphine biosynthesis genes and their potential to influence human being health. Neuro Endocrinol Lett. 2010;31:11–18. [PubMed] [Google Scholar]

5. Aliev G, Priyadarshini M, Reddy VP, et al. Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease. Curr Med Chem. 2014;21:2208–17. [PubMed] [Google Scholar]

6. Carvalho C, Machado N, Mota PC, et al. Blazon 2 diabetic and Alzheimer'southward affliction mice present like behavioral, cerebral, and vascular anomalies. J Alzheimers Dis. 2013;35:623–35. [PubMed] [Google Scholar]

7. Chong ZZ, Li F, Maiese K. Oxidative stress in the encephalon: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol. 2005;75:207–46. [PubMed] [Google Scholar]

viii. Ebadi One thousand, Govitrapong P, Sharma S, et al. Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson'south disease. Biol Signals Recept. 2001;10:224–53. [PubMed] [Google Scholar]

9. Kream RM, Mantione KJ, Casares FM, Stefano GB. Dumb expression of ATP-binding cassette transporter genes in diabetic ZDF rat claret. International Journal of Diabetes Research. 2014;three:49–55. [Google Scholar]

10. Kream RM, Mantione KJ, Casares FM, Stefano GB. Concerted dysregulation of 5 major classes of blood leukocyte genes in diabetic ZDF rats: A working translational profile of comorbid rheumatoid arthritis progression. International Journal of Prevention and Handling. 2014;3:17–25. [Google Scholar]

11. Wang F, Guo X, Shen X, et al. Vascular dysfunction associated with type 2 diabetes and Alzheimer'due south disease: A potential etiological linkage. Med Sci Monit Basic Res. 2014;20:118–29. [PMC free article] [PubMed] [Google Scholar]

12. Wang F, Stefano GB, Kream RM. Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: Etiological contribution to Complex Regional Pain Syndromes (Part I) Med Sci Monit. 2014;xx:1067–77. [PMC gratis commodity] [PubMed] [Google Scholar]

13. Wang F, Stefano GB, Kream RM. Epigenetic modification of DRG neuronal gene expression subsequent to nervus injury: Etiological contribution to Complex Regional Pain Syndromes (Part II) Med Sci Monit. 2014;20:1188–200. [PMC free article] [PubMed] [Google Scholar]

14. Panksepp J, Herman B, Conner R, et al. The biology of social attachments: sopiates convalesce separation distress. Biol Psychiatry. 1978;13:607–xviii. [PubMed] [Google Scholar]

15. Pierce RC, Kumaresan V. The mesolimbic dopamine organization: The final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev. 2006;thirty:215–38. [PubMed] [Google Scholar]

sixteen. Schmauss C, Emrich HM. Dopamine and the action of opiates: a reevaluation of the dopamine hypothesis of schizophrenia. With special consideration of the function of endogenous opioids in the pathogenesis of schizophrenia. Biol Psychiatry. 1985;20:1211–31. [PubMed] [Google Scholar]

17. Stepien A, Stepien M, Wlazel RN, et al. Assessment of the human relationship between lipid parameters and obesity indices in non-diabetic obese patients: a preliminary report. Med Sci Monit. 2014;twenty:2683–88. [PMC free article] [PubMed] [Google Scholar]

eighteen. Gohring I, Sharoyko VV, Malmgren S, et al. Chronic high glucose and pyruvate levels differentially affect mitochondrial bioenergetics and fuel-stimulated insulin secretion from clonal INS-1 832/13 cells. J Biol Chem. 2014;289:3786–98. [PMC gratis article] [PubMed] [Google Scholar]

19. Mantione KJ, Kream RM, Kuzelova H, et al. Comparison bioinformatic factor expression profiling methods: Microarray and RNA-Seq. Med Sci Monit Bones Res. 2014;twenty:138–41. [PMC costless article] [PubMed] [Google Scholar]

20. Kram KE, Finkel SE. Culture volume and vessel bear on long-term survival, mutation frequency, and oxidative stress of Escherichia coli. Appl Environ Microbiol. 2014;80:1732–38. [PMC gratuitous article] [PubMed] [Google Scholar]

21. Stefano GB, Kream RM. Hypoxia divers every bit a common culprit/initiation factor in mitochondrial-mediated proinflammatory processes. Med Sci Monit. 2015;21:1478–84. [PMC free article] [PubMed] [Google Scholar]

22. Guo R, Li Due west, Liu B, et al. Resveratrol protects vascular smooth muscle cells confronting high glucose-induced oxidative stress and jail cell proliferation in vitro. Med Sci Monit Basic Res. 2014;xx:82–92. [PMC free article] [PubMed] [Google Scholar]

23. Yildirim Five, Doganci Due south, Yesildal F, et al. Sodium nitrite provides angiogenic and proliferative effects in vivo and in vitro. Med Sci Monit Basic Res. 2015;21:41–46. [PMC free article] [PubMed] [Google Scholar]

24. Davila AF, Zamorano P. Mitochondria and the evolutionary roots of cancer. Phys Biol. 2013;x:026008. [PubMed] [Google Scholar]

25. Doeller JE, Grieshaber MK, Kraus DW. Chemolithoheterotrophy in a metazoan tissue: thiosulfate production matches ATP demand in ciliated mussel gills. J Exp Biol. 2001;204:3755–64. [PubMed] [Google Scholar]

26. Doeller JE, Kraus DW, Shick JM, Gnaiger E. Heat flux, oxygen flux, and mitochondrial redox state every bit a part of oxygen availability and ciliary activity in excised gills of Mytilus edulis. J Exp Zool. 1993;265:1–eight. [PubMed] [Google Scholar]

27. Tan DX, Manchester LC, Liu X, et al. Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin'due south primary function and evolution in eukaryotes. J Pineal Res. 2013;54:127–38. [PubMed] [Google Scholar]

28. Cruz S, Calado R, Serodio J, Cartaxana P. Itch leaves: photosynthesis in sacoglossan bounding main slugs. J Exp Bot. 2013;64:3999–4009. [PubMed] [Google Scholar]

29. Serodio J, Cruz S, Cartaxana P, Calado R. Photophysiology of kleptoplasts: photosynthetic apply of light past chloroplasts living in animal cells. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130242. [PMC free article] [PubMed] [Google Scholar]

30. de Vries J, Christa Thou, Gould SB. Plastid survival in the cytosol of animal cells. Trends Institute Sci. 2014;19:347–fifty. [PubMed] [Google Scholar]

31. Pennisi E. Microbiology. Modern symbionts inside cells mimic organelle evolution. Scientific discipline. 2014;346:532–33. [PubMed] [Google Scholar]

32. Handeler K, Wagele H, Wahrmund U, et al. Slugs' last meals: molecular identification of sequestered chloroplasts from different algal origins in Sacoglossa (Opisthobranchia, Gastropoda) Mol Ecol Res. 2010;10:968–78. [PubMed] [Google Scholar]

33. Kerney R, Kim Due east, Hangarter RP, et al. Intracellular invasion of light-green algae in a salamander host. Proc Natl Acad Sci Us. 2011;108:6497–502. [PMC free article] [PubMed] [Google Scholar]

35. Renato M, Pateraki I, Boronat A, Azcon-Bieto J. Lycopersicon esculentum fruit chromoplasts behave as respiratory bioenergetic organelles during ripening. Found Physiol. 2014;166:920–33. [PMC gratis article] [PubMed] [Google Scholar]

36. van Dongen JT, Licausi F. Oxygen sensing and signaling. Annu Rev Establish Biol. 2015;66:345–67. [PubMed] [Google Scholar]

37. Kleine T, Leister D. Emerging functions of mammalian and plant mTERFs. Biochim Biophys Acta. 2015;1847(9):786–97. [PubMed] [Google Scholar]

38. Maier UG, Zauner S, Woehle C, et al. Massively convergent development for ribosomal protein factor content in plastid and mitochondrial genomes. Genome Biol Evol. 2013;v:2318–29. [PMC gratuitous article] [PubMed] [Google Scholar]

39. Otten AB, Smeets HJ. Evolutionary divers role of the mitochondrial Deoxyribonucleic acid in fertility, disease and ageing. Hum Reprod Update. 2015 [Epub ahead of print] [PubMed] [Google Scholar]

40. Hedges SB, Chen H, Kumar S, et al. A genomic timescale for the origin of eukaryotes. BMC Evol Biol. 2001;1:4. [PMC free article] [PubMed] [Google Scholar]

41. Xavier JM, Rodrigues CM, Sola S. Mitochondria: Major regulators of neural development. Neuroscientist. 2015 [Epub ahead of print] [PubMed] [Google Scholar]

42. Stefano GB. Conformational matching: a possible evolutionary force in the evolvement of signal systems. In: Stefano GB, editor. CRC Handbook of comparative opioid and related neuropeptide mechanisms. Vol. 2. Boca Raton: CRC Press Inc; 1986. pp. 271–77. [Google Scholar]

43. Stefano GB. The evolvement of signal systems: conformational matching a determining force stabilizing families of point molecules. Comp Biochem Physiol C. 1988;xc:287–94. [PubMed] [Google Scholar]

44. Stefano GB. Stereospecificity as a determining forcefulness stabilizing families of signal molecules within the context of evolution. In: Stefano GB, Florey E, editors. Comparative aspects of Neuropeptide Function. Manchester: University of Manchester Press; 1991. pp. 14–28. [Google Scholar]

Articles from Medical Scientific discipline Monitor : International Medical Periodical of Experimental and Clinical Research are provided here courtesy of International Scientific Information, Inc.