J Infertil Reprod Biol, 2018, Volume 6, Issue 1, Pages: 1-3. https://doi.org/10.47277/JIRB/6(1)/1  
Mitochondrial Fatty Acid Transport System and its  
Relevance to Ovarian Function  
Mona Sharma  
Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi-110029, India  
Received: 06/12/2017  
Accepted: 1/03/2018  
Published: 20/03/2018  
Mitochondrial fatty acid oxidation is integral to folliculogenesis and oocyte maturation. Mitochondrial fatty acid transport system  
includes molecules such as 3-hydroxy-4-trimethylamino butyrate or carnitine, organic cation transporter novel 2 (OCTN2), carnitine  
palmitoyl transferase (CPT1), CPT2, and carnitine-acylcarnitine translocase (CACT). These are essential molecules that play an  
important role in the transport of activated long chain fatty acids from cytosol to the mitochondrial matrix where these subsequently  
undergo beta-oxidation. It has been well established that fatty acid metabolism is vital for follicles and oocyte growth. This review  
highlights the possible role of mitochondrial fatty transport acid system in ovarian function.  
Keywords: Oocytes, Carnitine, Mitochondria, Fatty acids  
acyl-carnitine by CPTI present in inner mitochondrial  
membrane (figure 1). Acyl-carnitine is transferred to matrix via  
CACT. After traversing membrane, acyl group is transferred by  
CPT2 from carnitine to CoA which then undergoes citric acid  
cycle. Carnitine is then shuttled back across membrane by  
CACT and the process is repeated (7). TMLHE (epsilon-  
trimethyllysine hydroxylase) is the gene encoding the first  
enzyme-trimethyl lysine dioxygenase/hydroxylase, catalyzing  
the rate limiting step of carnitine biosynthesis. Trimethyllysine  
Mitochondrial function is essential for various cellular  
activities including cell division and cell death or apoptosis (1).  
Mitochondrial role has also been proven in human fertility (2).  
Fertility is a key component of reproductive health in men and  
women. Infertility has become a global health issue. Prevalence  
of infertility in female is estimated to be 15% in India (3).  
Ovarian function is integral to female fertility. Ovarian  
folliculogenesis needs energy from various sources like  
glucose, lipids and amino acids. Maximum energy is derived  
from mitochondrial fatty acids oxidation (4). Role of  
mitochondrial fatty acid β-oxidation is important in acquisition  
of oocyte developmental competence.  
dioxygenase /hydroxylase is  
a non-heme ferrous iron  
hydroxylase and 2-oxoglutarate dependent. It is the only  
enzyme of carnitine biosynthesis located in the mitochondria  
whereas the other three are cytosolic. The encoded protein  
converts trimethyllysine (TML) into hydroxytrimethyllysine  
Mitochondrial Fatty Acid Transport System  
Mitochondrial fatty acid transport system includes  
molecules such as 3-hydroxy-4-trimethylamino butyrate or  
carnitine, organic cation transporter novel 2 (OCTN2),  
carnitine palmitoyl transferase (CPT1), CPT2, and carnitine-  
acylcarnitine translocase (CACT). The molecules play an  
important role in the transport of activated long chain fatty acids  
from cytosol to the mitochondrial matrix where these  
subsequently undergo beta-oxidation. Fatty acid transporter or  
carnitine plays an essential role in the transport of activated  
fatty acids across the inner mitochondrial membrane (5).  
Carnitine is 3-hydroxy-4-trimethylaminobutyrate and exists in  
L and D isomers. Normal serum L-carnitine levels are between  
HTML) Further,  
trimethylaminobutaraldehyde dehydrogenase converts HTML  
into trimethylamino- butaraldehyde (TAB).  
Hydroxytrimethyllysine aldolase converts TAB into  
trimethylaminobutyrate/butyrobetaine which is catalyzed by Ƴ-  
butyrobetaine dioxygenase and finally converted into carnitine  
Relevance to Ovarian Function  
Successful reproduction depends on competent oocyte  
capable of undergoing fertilization. Role of carnitine through  
fatty acid metabolism has also been established in oocyte growth  
and development. The antiapoptotic property of l-carnitine is to  
stabilize mitochondrial membrane thereby increasing supply of  
energy. Oocyte meiotic maturation needs energy from various  
sources like glucose, lipids and amino acids. Oocyte maturation  
includes cytoplasmic and nuclear events all of which are energy  
consuming and require adequate ATP (8). Oxidative stress is one  
of the mediators that affect quantity and quality of oocytes by  
inducing apoptosis. Antioxidant supplementation has been  
proved to protect oocytes against reactive oxygen species (ROS)  
and oxidative stress.  
5-50µM. Carnitine is synthesized from lysine and methionine  
mainly in kidney, liver and brain (6). Free carnitine was first  
isolated from bovine muscle and only L- isomer was found to  
be bioactive. L-carnitine is also involved in maintaining  
balance by removing accumulated toxic fatty acyl-CoA  
metabolites. Carnitine is reabsorbed in circulation by renal  
tubular active transport by OCTN2 transporter protein  
regulated by SLC22A5 gene. OCTN2 is essential for carnitine  
homeostasis. The fatty acids are first conjugated to form acyl  
CoA. This acyl group is then transferred to carnitine forming  
Corresponding author: Mona Sharma, Assistant Professor, Department of Reproductive Biology, All India Institute of Medical  
Sciences, New Delhi-110029, India. Contact No. 9968147821. Email address:dr.mona18sharma@gmail.com  
J Infertil Reprod Biol, 2018, Volume 6, Issue 1, Pages: 1-3. https://doi.org/10.47277/JIRB/6(1)/1  
Figure 1. Schematic diagram showing carnitine mediated transfer of fatty acids across mitochondrial membrane  
Carnitine is also an antioxidant that protects mitochondria  
from oxidative stress. The role of carnitine has been well proved  
in oocyte maturation. Fatty acid oxidation is critical for oocyte  
maturation as shown in mice (9). Inhibition of fatty acid oxidation  
with CPTI inhibitor etomoxir during in-vitro maturation delays  
oocyte meiotic maturation (10). Moreover, carnitine  
supplementation of culture media increases fatty acid oxidation  
that significantly improves oocyte quality in terms of fertilization  
and embryo development in mice and cows (11, 12). Fatty acid  
metabolism in cumulus cells has also been shown importance.  
There is enhanced expression of genes in cumulus cells related to  
fatty acid metabolism in mature oocytes as compared to immature  
oocytes (13). Increase in free fatty acid levels leads to  
mitochondrial dysfunction leading to cell death, oxidative stress  
and ROS generation. These effects are improved by carnitine  
treatment (14). Commonly used antioxidants are acetyl-L-  
carnitine (ALCAR), sodium citrate and α-lipoic acid (15, 16).  
ALCAR treatment of oocytes during in-vitro maturation (IVM)  
improves oocyte quality by increasing number of mature oocytes.  
This also improves normal spindle formation (17). Effects of fatty  
acid oxidation on nuclear maturation have also been shown in  
mice, cows and pigs (10). Variable ATP levels affect oocyte  
quality, embryo development and subsequent implantation (18).  
Mouse oocytes with inadequate ATP levels have also shown  
chromatin and microtubular abnormalities (19). Mitochondrion is  
also a signal transducer of apoptosis pathway. L-carnitine  
treatment has shown to inhibit apoptosis both in-vivo and in-vitro  
porcine oocytes (10).  
Clinical Implications and Future Prospects  
The association of abnormal functioning of fatty acid  
system has been observed in number of studies. CPT1A  
inhibition leads to decreased beta-oxidation and low number of  
blastocyst formation following oocyte fertilization (9). CPT2  
gene mutation was associated with infertility (23). Not much  
work has been done on SLC22A5 gene coding for OCTN2  
regulation.Role of CACT in reproduction is also not much  
elaborated. Few studies using microarray identified copy  
number variations in the TMLHE locus Xq28 in patients of  
premature ovarian failure (POF) (24).  
Fertility potential of a woman with POF is mostly  
compromised by the time when the clinical manifestations of  
hormonal decline are yet to appear (25). POF is a primary  
ovarian defect with symptoms of absent menarche or cessation  
of/irregular menstruation, infertility and symptoms of  
physiological menopause due to low estrogen levels before the  
age of 40 years. Infertility in POF is caused by decreased oocyte  
reserve due to accelerated follicular and oocyte atresia or  
decreased ovarian reserve since birth. POF constitutes roughly  
1% cases of infertility in females (26). Despite of multiple  
etiologies suggested such as genetic, metabolic, infections,  
autoimmune etc., POF remains idiopathic and untreated in most  
cases (27).  
By looking at the function of mitochondrial fatty acid  
system in beta-oxidation and role of fatty acid oxidation in  
follicular and oocyte development, association of  
mitochondrial fatty acid system in pathophysiology of POF can  
be suggested. The routine tests fail to detect POF at earlier  
stages where chances of fertility improvement may persist.  
20, 21). β-oxidation is important in acquisition of oocyte  
developmental competence and female fertility. L-carnitine  
supplementation has improved oocyte cytoskeleton damage and  
mitochondrial disruption (22). Beta-oxidation is required for  
oocyte meiotic resumption and nuclear maturation in mice and  
J Infertil Reprod Biol, 2018, Volume 6, Issue 1, Pages: 1-3. https://doi.org/10.47277/JIRB/6(1)/1  
Moreover, treatment options are lacking in POF. Therefore,  
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search on early diagnostic markers and treatment options is  
utmost important. The future research should focus creating  
POF disease models using factors regulating mitochondrial  
fatty acid transport system. Identification of novel gene  
mutations in SLC22A5, TMLHE, CPT1A, CPT2, CACT will  
help in structuring biomarker gene panel for early identification  
of idiopathic POF. Validation studies in larger number of  
cohorts can mark the gene panel as biomarker of metabolic  
etiology of POF. This will help in identifying POF at an earlier  
stage where fertility preservation is possible. Designing  
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Fatty acid metabolism being the most important energy  
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in ovarian disorders such as POF. Fatty acid transport system in  
mitochondria is integral for efficient beta oxidation. Therefore,  
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Ethical issue  
Authors are aware of, and comply with, best practice in  
publication ethics specifically with regard to authorship  
avoidance of guest authorship), dual submission, and  
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manipulation of figures, competing interests and compliance with  
policies on research ethics. Authors adhere to publication  
requirements that submitted work is original and has not been  
published elsewhere in any language.  
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Competing interests  
The authors declare that there is no conflict of interest that  
would prejudice the impartiality of this scientific work.  
Authors’ contribution  
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All authors of this study have a complete contribution for data  
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2. Mansour G, Abdelrazeik H, Sharma RK, et al. L-carnitine  
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