ISJ 12: 22-28, 2015    


ISJ 12: 22-28, 2015                                                                  ISSN 1824-307X 
 
 

REVIEW 
 
Anaerobically functioning mitochondria: evolutionary perspective on modulation of 
energy metabolism in Mytilus edulis 
 
GB Stefano1, 2, KJ Mantione1, FM Casares1, RM Kream1 
 
1Neuroscience Research Institute, State University of New York, College at Old Westbury, Old Westbury, NY, 
USA 
2Center for Molecular and Cognitive Neuroscience, 1st Faculty of Medicine, Charles University in Prague, Prague, 
Czech Republic 
 
 

   Accepted January 9, 2015 

 
Abstract 

The mitochondrion represents a compelling biological model of complex organelle development 
driven by evolutionary modification of permanently enslaved primordial purple non-sulphur bacteria. 
As an evolutionary modification, the dynamic nature of the mitochondrion has been observed to exhibit 
biochemical and functional variation, including the capacity for energy production driven by anaerobic 
respiratory mechanisms. In invertebrates, mitochondrial anaerobic respiration allows the organism to 
survive at a lower energy state while yielding more ATP than can be achieved by glycolysis alone. 
Furthermore, a preferred physiological state of lower energy production operationally yields diminished 
free radical generation, thereby offering a protective existential advantage. It has been established 
that energy production by the blue mussel, Mytilus edulis, is functionally dependent on anaerobic 
respiratory mechanisms within the mitochondrion. Importantly, under hypoxic conditions metabolic 
pathways in M. edulis have been demonstrated to synthesize and utilize amino acid adducts termed 
opines as chemically defined energy reserves. In addition to the utilization of opines as anaerobic 
metabolic intermediates by invertebrate organisms, opines were also discovered and characterized as 
metabolic intermediates in plant parasites, specifically crown gall tumors. A careful review of the 
biomedical literature indicates mechanistic similarities between anaerobically functioning mitochondria 
in M. edulis and crown gall tissues and metabolic processes in human tumors. The anaerobically 
functioning mitochondrion in M. edulis tissues is a potentially valuable high resolution model system 
for development of novel anticancer therapeutic agents. 
 
Key Words: anaerobic respiration; anaerobic mitochondria; opines; Mytilus edulis; mollusc 

 

 
Introduction 

 
Mitochondria represent an endosymbiont model 

of complex organelle development driven by 
evolutionary modification of permanently enslaved 
primordial purple non-sulphur bacteria (Gray et al., 
1999). From a teleological perspective, endosymbiotic 
enhancement of eukaryotic cellular energy 
requirements indicates a convergence of metabolic 
processes within the mitochondrial matrix for 
optimal synthesis of ATP from ADP and inorganic 
phosphate. Bacterial and mitochondrial ATP 
synthases (F-ATPases) require a defined membrane 
___________________________________________________________________________ 

 
Corresponding author: 
George B Stefano 
Neuroscience Research Institute 
State University of New York 
College at Old Westbury 
Old Westbury, NY, USA 
E-mail: gstefano@sunynri.org

 
 
potential to achieve transductive transmembrane 
proton-motive force across the inner membrane 
linked to high efficiency of ATP production (Stefano 
et al., 2012). This necessitates an evolutionarily 
driven retrofit of the bacterial plasma membrane into 
the inner mitochondrial membrane. The proton-
motive force is functionally coupled via mechanical 
transductive events within discrete protein subunits 
localized to the transmembrane domains of F-
ATPases and involves sequential protonation and 
deprotonation of glutamate side-chains of 
cytochrome c-subunits within functional pores. 
Evolutionary pressure is predicted to provide an 
existential advantage to the host eukaryotic cell at 
this primal level of energy production (Stefano et al., 
2012). Recent elegant work has confirmed this key 
contention by demonstrating an enhanced efficiency 
of 2.7 vs. 3.3 - 5 protons per synthesized ATP 
molecule by eukaryotic vs. prokaryotic F-ATPases, 

22 
 

mailto:gstefano@sunynri.org


 
 
Fig. 1 Anaerobic production and re-oxidation of the opine, octopine, in Mitylus edulis. Pyruvate is condensed with 
the amino acid, arginine, to produce octopine. The reaction is catalyzed by octopine dehydrogenase (OD). Opines 
are stored until oxygen becomes available to reverse this reaction and produce pyruvate for the Krebs cycle. 
 
 
 
 
 
respectively (Watt et al., 2010). 

Mechanistically, endosymbiosis has apparently 
resulted in seamless coupling of cytochrome c 
oxidase (COX) to F-ATPase for maximal ATP 
production in respiring mitochondria, thereby 
effecting essential partitioning of glycolytic and TCA 
cycle metabolic processes within discrete cellular 
domains. COX is an inner mitochondrial multi-
subunit enzyme complex expressed and assembled 
as a mosaic from nuclear and mitochondrial 
genomes. A recent review presents the case for 
COX as a key regulator of mitochondrial ATP 
production (Pierron et al., 2012). The authors 
propose that the evolutionarily driven addition of 
nuclear-encoded COX subunits provides the host 
eukaryotic cell with high order control over the 
ancestral activity of COX subunits encoded by 
mtDNA genes in the face of fluctuating 
mitochondrial oxygen tensions and potentially 
dangerous reactive oxygen species. 
 
Anaerobic respiration in invertebrates 

The intertidal habitat of the marine mussel, M. 
edulis, poses unique metabolic challenges to the 
survival of the species. During low tide, the mussel 
must close its valves to avoid water loss and 
therefore experiences hypoxic conditions. M. edulis 
has evolved to cope with hypoxia by switching to 
anaerobic respiration (de Zwaan et al., 1976; 
Connor et al., 2012). This strategy is not only 
employed by mussels; it has also been observed in 
other marine invertebrates (Hochachka et al., 1977), 
numerous other eukaryotes [see review (Muller et 
al., 2012)], plants (Igamberdiev et al., 2009; 
Shingaki-Wells et al., 2014), and of course in 
prokaryotes. To effectively mediate anaerobic 
metabolic demands, M. edulis synthesizes and 
utilizes amino acid adducts termed opines as 

chemically defined energy reserves (de Zwaan et 
al., 1976). 

Opines were first discovered in the mollusc, 
Octopus (Morizawa, 1927), notably the prototypic 
compound octopine, the enzymatically derived 
condensation product of arginine and pyruvate. In 
addition to the utilization of opines as anaerobic 
metabolic intermediates by invertebrate organisms, 
opines were also discovered and characterized as 
metabolic intermediates in plant parasites, 
specifically crown gall tumors (Holsters et al., 1978; 
Guyon et al., 1980; Toothman, 1982; Dessaux et al., 
1993). Synthesized opines are effectively stored 
until oxygen levels are sufficient to resume aerobic 
respiration followed by enzymatic oxidation to 
release pyruvate as an essential TCA cycle 
substrate (Grieshaber et al., 1994) (Fig. 1). The 
amino acids used in the biosynthesis of opines are 
alanine, arginine or glycine (Fields et al., 1980, 
Siegmund et al., 1983; Grieshaber et al., 1994). The 
enzyme required for production of octopine from 
arginine and pyruvate has recently been isolated 
and purified (Vazquez-Dorado et al., 2011). 
Presumably, this strategy evolved to maintain 
osmolality and to produce a by-product less acidic 
than lactate (Ballantyne, 2004). This metabolic 
pathway, like glycolysis, only produces 2 ATP per 
mole of glucose. 

 
Anaerobically functioning mitochondria in 
invertebrates 

In recent times the dynamic nature of the 
mitochondrion has been observed to exhibit 
biochemical and functional variation, including the 
capacity for anaerobic respiration (Muller et al., 
2012). In this regard, M. edulis has been well 
studied (Doeller et al., 2001; Connor et al., 2012). 
When a prolonged period of hypoxia leads to anoxia 

23 
 



 
 
Fig. 2 (adapted from (Muller et al., 2012) Anaerobic and aerobic metabolic pathways within the cytoplasm and 
mitochondria of the mussel, Mytilus edulis. Glucose can be converted to phosphoenolpyruvate and to pyruvate. 
Pyruvate can be used in the mitochondrial Krebs cycle or condensed with amino acids to produce opines. 
Phosphoenolpyruvate can be converted to malate before being simultaneously reduced to fumarate and oxidized 
to pyruvate (malate dismutation). Pyruvate can be used in the Krebs cycle. The fumarate is further reduced by 
fumarate reductase (FR) and rhodoquinone (RQ) to succinate. Succinate is then transformed into propionate as 
an end product. 
 
 
 
 
 
in the mussel, an additional metabolic pathway is 
employed instead of opine production (Woo et al., 
2011). Malate dismutation contains the favored 
reactions and malate’s reduction to fumarate, via a 
reaction that is essentially part of the Krebs cycle 
running in reverse, leads to the production of 
succinate (Muller et al., 2012). M. edulis utilizes 
fumarate reductase and rhodoquinone to reduce 
fumarate to succinate (Tielens et al., 2002). 
Succinate is further metabolized to propionate 
resulting in approximately 5 ATP (Tielens et al., 
2002) (Fig. 2). This process allows the organism to 
survive at a lower energy state while yielding more 
ATP than can be achieved by glycolysis alone. 
Furthermore, in this state of lower energy production 
there are less free radicals generated, offering a 
degree of protection while in this physiological state 
(Rivera-Ingraham et al., 2013). 

Interestingly, each tissue type in the mussel 
responds differently to hypoxia as a result of 
mitochondrial functional differences in gene 
expression. The gills, digestive glands, mantle, and 
adductor muscle have been shown to respond to 
hypoxia by switching to anaerobic respiration, 
(Ibarguren et al.,1989; Lushchak et al., 1997; 
Bacchiocchi et al., 2000, Doeller et al., 2001; Diaz-
Enrich et al., 2002). In the case of gill ciliated 
epithelium, which is most important for the survival 
of the individual, the metabolic process is kept on. 

This can be surmised by the fact that the gill cilia 
are densely packed with mitochondria (Paparo, 
1972). The ciliated gill epithelium of M. edulis has 
been studied not only for its ciliary activity but for its 
innervation as well (Paparo, 1972; Stefano et al., 
1975, 1976). This epithelium is innervated via 
serotoninergic and dopaminergic neurons, providing 
for cilio-excitation and cilio-inhibition, respectively. 
Clearly, this necessitates greater energy 
requirements, which may be difficult at intertidal 
intervals. We surmise this difficulty is overcome by 
way of nervous system integration of the tissue, 
exerting specific and rapid responses to respiratory 
and waste needs carried out by the ciliated 
epithelium (Stefano, 1990; Stefano et al., 1991). 
 
Anaerobically functioning mitochondria and cancer 
biology 

A careful review of the biomedical literature 
indicates functional similarities between anaerobic 
mitochondrial subtypes in M. edulis and crown gall 
tissue and metabolic processes in human tumors. 
Cancer cells utilize anaerobic energy metabolism 
under hypoxic, anoxic and even during normoxic 
conditions (Gonzalez et al., 2012; Amoedo et al., 
2013; Witkiewicz et al., 2013; Chen et al., 2014). It 
has been suggested that carcinogenic processes 
might target normal mitochondrial functioning and 
cause a disruption of the Krebs cycle and electron 

24 
 



transport enzymes (Gonzalez et al., 2012). It has 
been recently proposed that normative 
mitochondrial function in non-proliferating cells 
affects relatively high cytosolic ATP/ADP ratios 
resulting in functional inhibition of aerobic glycolysis 
(Maldonado et al., 2014). In contrast, the 
bioenergetics of the “Warburg” effect that has been 
extensively linked to the metabolic phenotype of 
numerous cancer cell types is characterized by 
enhanced aerobic glycolysis and suppression of 
aerobic mitochondrial metabolism (Gonzalez et al., 
2012; Amoedo et al., 2013; Witkiewicz et al., 2013; 
Chen et al., 2014). Furthermore, aerobic respiration 
in proliferating cells leads to deleterious production 
of free radicals that can damage DNA and proteins. 
Accordingly, free radical damage is proposed to 
exacerbate compromised mitochondrial functioning 
thereby diminishing the existential viability of cancer 
cells. Along these lines, Davila and Zamarano 
(2013) posit that cancer can be viewed as a cell that 
has phenotypically reverted to the last common 
eukaryotic ancestor of the host cell. They surmise 
that a cancer cell is functioning as a facultative 
anaerobic microbe with unlimited replication 
potential (Davila and Zamarano, 2013). 
Interestingly, anaerobic mitochondria in gill cilia of 
M. edulis have evolved to utilize the phenotype of a 
facultative anaerobe (Doeller et al., 1993, 2001). 
 
Mytilus mitochondrial DNA, tRNA and a link to 
cancer 

For over a decade, an ostensibly unresolved 
issue relating to essential genes expressed by 
mitochondrial DNA (mtDNA) from M. edulis and 
related species of marine mussels is the absence of 
a traditionally defined gene encoding subunit 8 of 
the mitochondrial ATP synthase complex (ATP8) 
(Boore, et al., 2004; Breton et al., 2010; Smietanka 
et al., 2010). The protein expressed by the ATP8 
gene has been established as an integral 
component of the ATP synthase stator stalk in yeast 
and all metazoan phyla and is essential for coupled 
ATP production within the mitochondrial matrix. 
Recently, two laboratories have independently 
defined an open reading frame (ORF) 
corresponding to a never before annotated ATP8 
variant in the mtDNA of several Mytilus species and 
have speculated that evolutionary resolution of 
mtDNA contributions by both male and female 
underlies its novel representation within the 
mitochondrial genome (Breton et al., 2010; 
Smietanka et al., 2010). A very recent publication 
reinforces the functional role of ATP8 mtDNA gene 
expression in the process of carcinogenesis 
(Grzybowska-Szatkowska et al., 2014). Five 
identified mutations and polymorphisms of the ATP8 
gene were identified in tissues obtained from breast 
cancer patients, thereby supporting the contention 
that functional modification/impairment of an 
essential subunit of the mitochondrial ATP synthase 
complex represents causative factor in 
carcinogenesis. 

Another interesting characteristic of Mytilus 
mitochondrial genome is the presence of an 
additional novel methionyl tRNA. Its UAU anticodon 
makes it unique among taxa (Hoffmann et al.,1992; 
Boore et al., 2004). The presence of this additional 

tRNA raises questions in regard to potential 
similarities with tumor cells since these tend to 
exhibit elevated levels of initiator methionyl tRNA 
expression (Kanduc, 1997; Kanduc et al., 1997; 
Marshall et al., 2008; Pavon-Eternod et al., 2009; 
Zhou et al., 2009). It has been postulated that 
altering the tRNA expression profile in cells might 
influence the regulation of translation of growth 
factors, proto-oncogenes and other proteins 
involved in cell cycle (Kanduc, 1997; Marshall et al., 
2008; Kolitz et al., 2009; Pavon-Eternod et al., 
2013). In particular, it has been demonstrated that 
increasing the levels of initiator tRNAmet caused a 
concomitant elevation of other tRNA molecules, 
resulting in increased metabolic activity and cell 
proliferation (Pavon-Eternod et al., 2013). 
Accordingly, after partial hepatectomy, levels of 
initiator tRNAmet increase in rat hepatocytes 
compared to those of elongator tRNAmet during cell-
cycle progression (Kanduc, 1997). Similar tRNAmet 
pattern shift was observed in human colorectal and 
gastro-intestinal tumors (Kanduc et al.,1997). 
Moreover, in embryonic fibroblasts from mice, 
overexpression of initiator tRNA resulted in 
induction of tumorigenesis (Marshall et al., 2008), 
and in breast cancer and multiple myeloma cell lines 
initiator tRNA levels were also found to be elevated 
(Pavon-Eternod et al., 2009; Zhou et al., 2009). 
 
Mytilus as a model to study cancer 

In humans, the v-Ki-ras2 Kirsten rat sarcoma 
viral oncogene homolog (KRAS) gene encodes a 
small GTPase involved in key regulatory signaling 
cascades (Franks et al., 1987) and in tumorigenesis 
(Chetty et al., 2013). Amplification of KRAS gene 
expression and/or oncogenic activating gain-of-
function KRAS mutations have been functionally 
linked to enhanced growth, survival, and metastasis 
of major classes of human tumor types included in 
small-cell lung cancer (Minuti et al., 2013) colorectal 
cancer (Brand et al., 2012), pancreatic cancer (di 
Magliano et al., 2013, Fang et al., 2013), and 
intrahepatic cholangiocarcinoma (Robertson et al., 
2013). Of equivalent importance, dysregulation of 
the cellular epidermal growth factor receptor 
(EGFR) signaling pathway has been demonstrated 
to be critically important in promoting tumor growth, 
survival, and metastasis in human tumors (Goffin et 
al., 2013) and development of several frontline 
anticancer therapeutic agents have attempted to 
achieve efficacious selective targeting of the 
oncogenic EGFR signaling pathway (Kohler et al., 
2013). Recent studies indicate that KRAS 
tumorigenicity is functionally linked to the “Warburg” 
phenotype favoring a high rate of aerobic glycolysis 
and anaerobic mitochondrial function (Weinberg et 
al., 2010). This establishes the facultative anaerobic 
mitochondrion in M. edulis tissues as a potentially 
valuable high resolution model system for the 
development of novel anticancer therapeutic agents. 
 
Conclusions 

 
This review documents the phenomenon and 

existence of anaerobically functioning mitochondria 
in M. edulis as a model for invertebrate energy 
generating systems. In this regard, this mechanism 

25 
 



is used to benefit the organisms when large 
amounts of energy translocation are not present. It 
is clear Mytilus may use this pathway to survive 
when an abundant source of oxygen is not present 
e.g., intertidal periodicity. Accordingly, if 
mitochondria represents evolutionary defined 
endosymbiont organelles, they have retained part of 
the anaerobic process associated with bacteria. 
This dynamic capacity would have survival value 
under hypoxic environmental conditions. In part, we 
surmise, that dysfunctional mitochondria in cancer 
cells may have their origin in the early evolution of 
eukaryotic cells by retaining this information and/or 
processes to implement this phenomenon in times 
of stress. However, in metastatic processes this 
pathway may emerge due to poor chemical 
messenger regulation. Importantly, Mytilus may yet 
be another invertebrate that can be used as a model 
system because of its broad scope of energy 
balance and dynamic capacity to adapt. 
 
Acknowledgements 

This work, in part, was supported by 
Mitogenetics, LLC. (Sioux Falls, South Dakota). 
 
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