The inner mitochondrial membrane fission protein MTP18 serves as a mitophagy receptor to prevent apoptosis in oral cancer.

MTP18 (also known as MTFP1), an inner mitochondrial membrane protein, plays a vital role in maintaining mitochondrial morphology by regulating mitochondrial fission. Here, we found that MTP18 functions as a mitophagy receptor that targets dysfunctional mitochondria into autophagosomes for elimination. Interestingly, MTP18 interacts with members of the LC3 (also known as MAP1LC3) family through its LC3-interacting region (LIR) to induce mitochondrial autophagy. Mutation in the LIR motif (mLIR) inhibited that interaction, thus suppressing mitophagy. Moreover, Parkin or PINK1 deficiency abrogated mitophagy in MTP18-overexpressing human oral cancer-derived FaDu cells. Upon exposure to the mitochondrial oxidative phosphorylation uncoupler CCCP, MTP18[mLIR]-FaDu cells showed decreased TOM20 levels without affecting COX IV levels. Conversely, loss of Parkin or PINK1 resulted in inhibition of TOM20 and COX IV degradation in MTP18[mLIR]-FaDu cells exposed to CCCP, establishing Parkin-mediated proteasomal degradation of outer mitochondrial membrane as essential for effective mitophagy. We also found that MTP18 provides a survival advantage to oral cancer cells exposed to cellular stress and that inhibition of MTP18-dependent mitophagy induced cell death in oral cancer cells. These findings demonstrate that MTP18 is a novel mitophagy receptor and that MTP18-dependent mitophagy has pathophysiologic implications for oral cancer progression, indicating inhibition of MTP18-mitophagy could thus be a promising cancer therapy strategy.

Imperative connotation of SODs in cancer: Emerging targets and multifactorial role of action.

Superoxide dismutase (SOD) is a crucial enzyme responsible for the redox homeostasis inside the cell. As a part of the antioxidant defense system, it plays a pivotal role in the dismutation of the superoxide radicals ( O 2 - $$ {{\mathrm{O}}_2}^{-} $$ ) generated mainly by the oxidative phosphorylation, which would otherwise bring out the redox dysregulation, leading to higher reactive oxygen species (ROS) generation and, ultimately, cell transformation, and malignancy. Several studies have shown the involvement of ROS in a wide range of human cancers. As SOD is the key enzyme in regulating ROS, any change, such as a transcriptional change, epigenetic remodeling, functional alteration, and so forth, either activates the proto-oncogenes or aberrant signaling cascades, which results in cancer. Interestingly, in some cases, SODs act as tumor promoters instead of suppressors. Furthermore, SODs have also been known to switch their role during tumor progression. In this review, we have tried to give a comprehensive account of SODs multifactorial role in various human cancers so that SODs-based therapeutic strategies could be made to thwart cancers.

Inflammasomes in cancer: Effect of epigenetic and autophagic modulations.

Tumour-promoting inflammation is a critical hallmark in cancer development, and inflammasomes are well-known regulators of inflammatory processes within the tumour microenvironment. Different inflammasome components along with the adaptor, apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC), and the effector, caspase-1, have a significant influence on tumorigenesis but in a tissue-specific and stage-dependent manner. The downstream products of inflammasome activation, that is the proinflammatory cytokines such as IL-1ß and IL-18, regulate tissue homeostasis and induce antitumour immune responses, but in contrast, they can also favour cancer growth and proliferation by directing various oncogenic signalling pathways in cancer cells. Moreover, different epigenetic mechanisms, including DNA methylation, histone modification and noncoding RNAs, control inflammasomes and their components by regulating gene expression during cancer progression. Furthermore, autophagy, a master controller of cellular homeostasis, targets inflammasome-induced carcinogenesis by maintaining cellular homeostasis and removing potential cancer risk factors that promote inflammasome activation in support of tumorigenesis. Here, in this review, we summarize the effect of inflammasome activation in cancers and discuss the role of epigenetic and autophagic regulatory mechanisms in controlling inflammasomes. A proper understanding of the interactions among these key processes will be useful for developing novel therapeutic regimens for targeting inflammasomes in cancer.

Autophagy-modulating phytochemicals in cancer therapeutics: Current evidences and future perspectives.

Autophagy is an intracellular catabolic self-cannibalism that eliminates dysfunctional cytoplasmic cargos by the fusion of cargo-containing autophagosomes with lysosomes to maintain cyto-homeostasis. Autophagy sustains a dynamic interlink between cytoprotective and cytostatic function during malignant transformation in a context-dependent manner. The antioxidant and immunomodulatory phyto-products govern autophagy and autophagy-associated signaling pathways to combat cellular incompetence during malignant transformation. Moreover, in a close cellular signaling circuit, autophagy regulates aberrant epigenetic modulation and inflammation, which limits tumor metastasis. Thus, manipulating autophagy for induction of cell death and associated regulatory phenomena will embark on a new strategy for tumor suppression with wide therapeutic implications. Despite the prodigious availability of lead pharmacophores in nature, the central autophagy regulating entities, their explicit target, as well as pre-clinical and clinical assessment remains a major question to be answered. In addition to this, the stage-specific regulation of autophagy and mode of action with natural products in regulating the key autophagic molecules, control of tumor-specific pathways in relation to modulation of autophagic network specify therapeutic target in caner. Moreover, the molecular pathway specificity and enhanced efficacy of the pre-existing chemotherapeutic agents in co-treatment with these phytochemicals hold high prevalence for target specific cancer therapeutics. Hence, the multi-specific role of phytochemicals in a cellular and tumor context dependent manner raises immense curiosity for investigating of novel therapeutic avenues. In this perspective, this review discusses about diverse implicit mechanisms deployed by the bioactive compounds in diagnosis and therapeutics approach during cancer progression with special insight into autophagic regulation.

Lysosome signaling in cell survival and programmed cell death for cellular homeostasis.

Recent developments in lysosome biology have transformed our view of lysosomes from static garbage disposals that can also act as suicide bags to decidedly dynamic multirole adaptive operators of cellular homeostasis. Lysosome-governed signaling pathways, proteins, and transcription factors equilibrate the rate of catabolism and anabolism (autophagy to lysosomal biogenesis and metabolite pool maintenance) by sensing cellular metabolic status. Lysosomes also interact with other organelles by establishing contact sites through which they exchange cellular contents. Lysosomal function is critically assessed by lysosomal positioning and motility for cellular adaptation. In this setting, mechanistic target of rapamycin kinase (MTOR) is the chief architect of lysosomal signaling to control cellular homeostasis. Notably, lysosomes can orchestrate explicit cell death mechanisms, such as autophagic cell death and lysosomal membrane permeabilization-associated regulated necrotic cell death, to maintain cellular homeostasis. These lines of evidence emphasize that the lysosomes serve as a central signaling hub for cellular homeostasis.

Chemotherapeutic efficacy of curcumin and resveratrol against cancer: Chemoprevention, chemoprotection, drug synergism and clinical pharmacokinetics.

The frequent inefficiency of conventional cancer therapies due to drug resistance, non-targeted drug delivery, chemotherapy-associated toxic side effects turned the focus to bioactive phytochemicals. In this context, curcumin and resveratrol have emerged as potent chemopreventive and chemoprotective compounds modulating apoptotic and autophagic cell death pathways in cancer in vitro and in vivo. As synergistic agents in combination with clinically established anticancer drugs, the enhanced anticancer activity at reduced chemotherapy-associated toxicity towards normal organs can be explained by improved pharmacokinetics, pharmacodynamics, bioavailability and metabolism. With promising preclinical and clinical applications, the design of drug-loaded nanoparticles, nanocarriers, liposomes and micelles have gained much attention to improve target specificity and drug efficacy. The present review focuses on the molecular modes of chemoprevention, chemoprotection and drug synergism with special emphasis to preclinical and clinical applications, pharmacokinetics, pharmacodynamics and advanced drug delivery methods for the development of next-generation personalized cancer therapeutics.

Algal Phlorotannins as Novel Antibacterial Agents with Reference to the Antioxidant Modulation: Current Advances and Future Directions.

The increasing drug resistance of infectious microorganisms is considered a primary concern of global health care. The screening and identification of natural compounds with antibacterial properties have gained immense popularity in recent times. It has previously been shown that several bioactive compounds derived from marine algae exhibit antibacterial activity. Similarly, polyphenolic compounds are generally known to possess promising antibacterial capacity, among other capacities. Phlorotannins (PTs), an important group of algae-derived polyphenolic compounds, have been considered potent antibacterial agents both as single drug entities and in combination with commercially available antibacterial drugs. In this context, this article reviews the antibacterial properties of polyphenols in brown algae, with particular reference to PTs. Cell death through various molecular modes of action and the specific inhibition of biofilm formation by PTs were the key discussion of this review. The synergy between drugs was also discussed in light of the potential use of PTs as adjuvants in the pharmacological antibacterial treatment.

The emerging, multifaceted role of mitophagy in cancer and cancer therapeutics.

Mitophagy is an evolutionarily conserved cellular process which selectively eliminates dysfunctional mitochondria by targeting them to the autophagosome for degradation. Dysregulated mitophagy results in the accumulation of damaged mitochondria, which plays an important role in carcinogenesis and tumor progression. The role of mitophagy receptors and adaptors including PINK1, Parkin, BNIP3, BNIP3L/NIX, and p62/SQSTM1, and the signaling pathways that govern mitophagy are impaired in cancer. Furthermore, the contribution of mitophagy in regulating the metabolic switch may establish a balance between aerobic glycolysis and oxidative phosphorylation for cancer cell survival. Moreover, ROS-driven mitophagy achieves different goals depending on the stage of tumorigenesis. Mitophagy promotes plasticity in the cancer stem cell through the metabolic reconfiguration for better adaption to the tumor microenvironment. In addition, the present review sheds some light on the role of mitophagy in stemness and differentiation during the transition of cell's fate, which could have a crucial role in cancer progression and metastasis. In conclusion, this review deals with the detailed molecular mechanisms underlying mitophagy, along with highlighting the dual role of mitophagy in different aspects of cancer, suggesting it as a possible target in the mitophagy-modulated cancer therapy.

Epigenetic modifications of autophagy in cancer and cancer therapeutics.

Epigenetic alterations, such as DNA methylation, histone modifications and miRNAs, have a significant role play in malignant cellular transformation and metastasis. On the other hand, autophagy has been reported to perform context-dependent roles in cancer; at times, it becomes lethal and abolishes tumorigenesis, whereas, at other instances, it protects cancer cells by providing a rescue mechanism under adverse conditions. Although epigenetics and autophagy are two important and independent cellular processes, various oncogenic and oncosuppressor proteins involve autophagy through epigenetic modifications and different signaling pathways, thereby regulating tumor growth and therapeutic response. Moreover, the importance of epigenetic modification of autophagy in cancer is reflected through its involvement in cancer stem cell maintenance, which in turn, contributes to tumor cell viability during dormancy leading to tumor recurrence. The effects of epigenetic modifications of autophagy in cancer is still ambiguous and less acknowledged; therefore, efforts have been made to understand its detail underlying mechanism to unveil new targets and avenues for better prognosis and diagnosis of cancer.

Apoptosis and autophagy modulating dietary phytochemicals in cancer therapeutics: Current evidences and future perspectives.

The global incidence of cancer and cancer-related mortality is expected to rise in recent years despite advancements in cancer diagnosis and therapeutics. Increasing evidences of decrypting molecular mechanisms underlying cancer progression have commanded the tremendous development of synthetic anticancer drugs. With limitations in the current conventional cancer therapeutic approaches, the non-nutritive dietary phytochemicals have emerged as potent modulators of apoptosis and autophagy associated key signaling pathways in various cancer cells. The dynamic regulation of apoptosis and autophagy by phytochemicals in cancer are identified as promising therapeutic candidates with minimal cytotoxicity and enhanced biological activity. Dietary phytochemicals and their synthetic analogs have exhibited potency in the modulation of apoptosis and autophagy in several cancer cells as individuals or in combination with pre-existing FDA (Food and Drug Administration) approved anticancer drugs. In the current generation of medical science, developing precision and personalized medicine and their consumption as food supplements will hold high prevalence in cancer therapeutics. Hence understating the impact of dietary phytochemicals on human health and their molecular mechanism will thrive a new horizon in cancer therapeutics. Hence, this review has emphasized the role of apoptotic/autophagy modulating dietary phytochemicals in cancer therapy, their preclinical and clinical applications and the future direction of enhanced nano-formulation for better clinical efficacy.

Demarcating antioxidant response against aluminum induced oxidative stress in Westiellopsis prolifica Janet 1941.

Aluminum metal pollution is considered as a primary limiting factor that reduced crop yield in South Asian subtropical country like India. In national context, Odisha contributes around more than 40% of total ore availability. Moreover, industrial mining and smelting aid are major concern for aluminum metal toxicity in territorial vicinity affecting the soil fertility, ecosystem and human health through food chain. The aluminum metal accumulation limits the soil fertility by antagonistic regulation of photosynthetic and nitrogen fixing microbiota. The increasing concern regarding aluminum pollution enterprise critical investigations for their bioremediation in contamination sites. In this notion, the current study was hypothesized to decrypt the rate limiting factors, their explicit mode of action and intracellular detoxification in a cyanobacterium, i.e., Westiellopsis prolifica isolated from ash pond of NALCO (National Aluminum Company Limited), Angul, Odisha. In the experimental setup, treatment with different concentrations of AlCl3 (0-0.1 mM) was marked a decline in the growth of the strain due to the adverse regulation of photosynthetic pigments. However, the enforcement of catalase (CAT), ascorbate peroxidase (APX), superoxide dismutase (SOD), guaiacol peroxidase (GPX) and glutathione reductase (GR) was critical for sustaining strain viability under oxidative imbalance. The observation of an increase in the antioxidant enzyme and MDA content was evident to sustain strain viability under such oxidative imbalance. The outcome of the anticipated study was apparent to demonstrate a colossal interlink between Al mediated induction of oxidative stress and their cellular detoxification via intracellular antioxidant enzymes and removal of H2O2 accumulation in cyanobacterium, W. prolifica. Statement of novelty Aluminum metal toxicity renders growth of Westiellopsis prolifica via affecting photosynthesis associated pigments. Westiellopsis prolifica deploys antioxidant defense enzymes to combat against aluminum mediated oxidative upset. Intracellular antioxidant enzymes provoke cellular survival of Westiellopsis prolifica under excessive uptake of aluminum in contaminated habitats.

Preliminary Investigation of the Antioxidant, Anti-Diabetic, and Anti-Inflammatory Activity of Enteromorpha intestinalis Extracts.

Marine algae are a promising source of potent bioactive agents against oxidative stress, diabetes, and inflammation. However, the possible therapeutic effects of many algal metabolites have not been exploited yet. In this regard, we explored the therapeutic potential of Enteromorpha intestinalis extracts obtained from methanol, ethanol, and hexane, in contrasting oxidative stress. The total phenolic (TPC) and flavonoids (TFC) content were quantified in all extracts, with ethanol yielding the best values (about 60 and 625 mg of gallic acid and rutin equivalents per gram of extract, respectively). Their antioxidant potential was also assessed through DPPH•, hydroxyl radical, hydrogen peroxide, and superoxide anion scavenging assays, showing a concentration-dependent activity which was greater in the extracts from protic and more polar solvents. The α-amylase and α-glucosidase activities were estimated for checking the antidiabetic capacity, with IC50 values of about 3.8 µg/mL for the methanolic extract, almost as low as those obtained with acarbose (about 2.8 and 3.3 µg/mL, respectively). The same extract also showed remarkable anti-inflammatory effect, as determined by hemolysis, protein denaturation, proteinase and lipoxygenase activity assays, with respectable IC50 values (about 11, 4, 6, and 5 µg/mL, respectively), also in comparison to commercially used drugs, such as acetylsalicylic acid.

Deacetylation of LAMP1 drives lipophagy-dependent generation of free fatty acids by Abrus agglutinin to promote senescence in prostate cancer.

Therapy-induced senescence in cancer cells is an irreversible antiproliferative state, which inhibits tumor growth and is therefore a potent anti-neoplastic mechanism. In this study, low doses of Abrus agglutinin (AGG)-induced senescence through autophagy in prostate carcinoma cells (PC3) and inhibited proliferation. The inhibition of autophagy with 3-methyl adenine reversed AGG-induced senescence, thus confirming that AGG-triggered senescence required autophagy. AGG treatment also led to lipophagy-mediated accumulation of free fatty acids (FFAs), with a concomitant decrease in the number of lipid droplets. Lalistat, a lysosomal acid lipase inhibitor, abrogated AGG-induced lipophagy and senescence in PC3 cells, indicating that lipophagy is essential for AGG-induced senescence. The accumulation of FFAs increased reactive oxygen species generation, a known facilitator of senescence, which was also reduced in the presence of lalistat. Furthermore, AGG upregulated silent mating type information regulator 2 homolog 1 (SIRT1), while the presence of sirtinol reduced autophagy flux and the senescent phenotype in the AGG-treated cells. Mechanistically, AGG-induced cytoplasmic SIRT1 deacetylated a Lys residue on the cytoplasmic domain of lysosome-associated membrane protein 1 (LAMP1), an autolysosomal protein, resulting in lipophagy and senescence. Taken together, our findings demonstrate a novel SIRT1/LAMP1/lipophagy axis mediating AGG-induced senescence in prostate cancer cells.

Enteromorpha compressa extract induces anticancer activity through apoptosis and autophagy in oral cancer.

Marine algae are an auspicious source of innovative bioactive compounds containing possible therapeutic agents against mammalian cancers. However, the mechanism by which bioactive algal compounds exhibit anticancer activity against oral squamous cell carcinoma (OSCC) is scant. The main objective of the current study was to explore the properties of the Enteromorpha compressa solvent extracts that induced autophagy and apoptosis with reference to their potent phytochemical and antioxidant properties. The presence of bioactive compounds were confirmed by UV and FT-IR spectroscopy. The free radical scavenging activity were analyzed by evaluating H2O2, DPPH, superoxide and hydroxyl activity. The anticancer activities of the extracts were investigated by employing clonogenic and scratch assay. The apoptosis potential was evaluated by DAPI and MMP by Rh123 fluorescence assay. Moreover, the CAT, SOD, GPX, APX, and GR activities were measured. The autophagy potential was evaluated by LC3 puncta formation, acridine orange in addition to LysoTracker staining. The present investigation revealed that the methanolic extract of E. compressa elicited robust free radical scavenging activity that discerns its antiproliferative potency. Moreover, the methanolic algal extract boosted intrinsic apoptosis against OSCC by downregulating protective antioxidant enzymes. Furthermore, it also revealed induction of autophagy to promote cell death in oral cancer cells. The presence of novel bioactive compounds in E. compressa has uncovered possible therapeutic value against OSCC by modulating antioxidant defense system, apoptosis and autophagy that could be used to explore very competent algal candidates for the development of potential alternative anticancer drugs.

Bioactive compounds from marine invertebrates as potent anticancer drugs: the possible pharmacophores modulating cell death pathways.

Marine invertebrates are extremely diverse, largely productive, untapped oceanic resources with chemically unique bioactive lead compound contributing a wide range of screening for the discovery of anticancer compounds. The lead compounds have unfurled an extensive array of pharmacological properties owing to the presence of polyphenols, alkaloids, terpenoids and other secondary metabolites. The antioxidant, immunomodulatory and anti-tumor activities exhibited, are possibly regulated by the apoptosis induction, scavenging of ROS and modulation of cellular signaling pathways to defy the cellular deafness during carcinogenesis. Despite the enriched bioactive compounds, the marine invertebrates are largely unexplored as identification, screening, pre-clinical and clinical assessment of lead compounds and their synthetic analogs remain a major task to be solved. In the current review, we focus on the principle strategy and underlying mechanisms deployed by the bioactive anticancer compounds derived from marine invertebrates to combat cancer with special insight into the cell death mechanism.

Intricate role of mitochondrial lipid in mitophagy and mitochondrial apoptosis: its implication in cancer therapeutics.

The efficacy of chemotherapy is mostly restricted by the drug resistance developed during the course of cancer treatment. Mitophagy, as a pro-survival mechanism, crucially maintains mitochondrial homeostasis and it is one of the mechanisms that cancer cells adopt for their progression. On the other hand, mitochondrial apoptosis, a precisely regulated form of cell death, acts as a tumor-suppressive mechanism by targeting cancer cells. Mitochondrial lipids, such as cardiolipin, ceramide, and sphingosine-1-phosphate, act as a mitophageal signal for the clearance of damaged mitochondria by interacting with mitophagic machinery as well as activate mitochondrial apoptosis via the release of cytochrome c into the cytoplasm. In the recent time, the lipid-mediated lethal mitophagy has also been used as an alternative approach to abolish the survival role of lipid in cancer. Therefore, by targeting mitochondrial lipids in cancer cells, the detailed mechanism linked to drug resistance can be unraveled. In this review, we precisely discuss the current knowledge about the multifaceted role of mitochondrial lipid in regulating mitophagy and mitochondrial apoptosis and its application in effective cancer therapy.

Dysregulation of histone deacetylases in carcinogenesis and tumor progression: a possible link to apoptosis and autophagy.

Dysregulation of the epigenome and constitutional epimutation lead to aberrant expression of the genes, which regulate cancer initiation and progression. Histone deacetylases (HDACs), which are highly conserved in yeast to humans, are known to regulate numerous proteins involved in the transcriptional regulation of chromatin structures, apoptosis, autophagy, and mitophagy. In addition, a non-permissive chromatin conformation is created by HDACs, preventing the transcription of the genes encoding the proteins associated with tumorigenesis. Recently, an expanding perspective has been reported from the clinical trials with HDACis (HDAC inhibitors), which has emerged as a determining target for the study of the detailed mechanisms underlying cancer progression. Therefore, the present review focuses on the comprehensive lucubration of post-translational modifications and the molecular mechanisms through which HDACs alter the ambiguities associated with epigenome, with particular insights into the initiation, progression, and regulation of cancer.

Bioactive Metabolites from Marine Algae as Potent Pharmacophores against Oxidative Stress-Associated Human Diseases: A Comprehensive Review.

In addition to cancer and diabetes, inflammatory and ROS-related diseases represent one of the major health problems worldwide. Currently, several synthetic drugs are used to reduce oxidative stress; nevertheless, these approaches often have side effects. Therefore, to overcome these issues, the search for alternative therapies has gained importance in recent times. Natural bioactive compounds have represented, and they still do, an important source of drugs with high therapeutic efficacy. In the ''synthetic'' era, terrestrial and aquatic photosynthetic organisms have been shown to be an essential source of natural compounds, some of which might play a leading role in pharmaceutical drug development. Marine organisms constitute nearly half of the worldwide biodiversity. In the marine environment, algae, seaweeds, and seagrasses are the first reported sources of marine natural products for discovering novel pharmacophores. The algal bioactive compounds are a potential source of novel antioxidant and anticancer (through modulation of the cell cycle, metastasis, and apoptosis) compounds. Secondary metabolites in marine Algae, such as phenolic acids, flavonoids, and tannins, could have great therapeutic implications against several diseases. In this context, this review focuses on the diversity of functional compounds extracted from algae and their potential beneficial effects in fighting cancer, diabetes, and inflammatory diseases.

Plant lectins in cancer therapeutics: Targeting apoptosis and autophagy-dependent cell death.

Plant lectins are non-immunoglobin in nature and bind to the carbohydrate moiety of the glycoconjugates without altering any of the recognized glycosyl ligands. Plant lectins have found applications as cancer biomarkers for recognizing the malignant tumor cells for the diagnosis and prognosis of cancer. Interestingly, plant lectins contribute to inducing cell death through autophagy and apoptosis, indicating their potential implication in cancer inhibitory mechanism. In the present review, anticancer activities of major plant lectins have been documented, with a detailed focus on the signaling circuit for the possible molecular targeted cancer therapy. In this context, several lectins have exhibited preclinical and clinical significance, driving toward therapeutic potential in cancer treatment. Moreover, several plant lectins induce immunomodulatory activities, and therefore, novel strategies have been established from preclinical and clinical investigations for the development of combinatorial treatment consisting of immunotherapy along with other anticancer therapies. Although the application of plant lectins in cancer is still in very preliminary stage, advanced high-throughput technology could pave the way for the development of lectin-based complimentary medicine for cancer treatment.

Mitochondrial Heterogeneity in Stem Cells.

Mitochondria are customarily acknowledged as the powerhouse of the cell by virtue of their indispensable role in cellular energy production. In addition, it plays an important role in pluripotency, differentiation, and reprogramming. This review describes variation in the stem cells and their mitochondrial heterogeneity. The mitochondrial variation can be described in terms of structure, function, and subcellular distribution. The mitochondria cristae development status and their localization patterns determine the oxygen consumption rate and ATP production which is a central controller of stem cell maintenance and differentiation. Generally, stem cells show spherical, immature mitochondria with perinuclear distribution. Such mitochondria are metabolically less energetic and low polarized. Moreover, mostly glycolytic energy production is found in pluripotent stem cells with a variation in naïve stem cells which perform oxidative phosphorylation (OXPHOS). This article also describes the structural and functional journey of mitochondria during development. Future insight into underlying mechanisms associated with such alternation in mitochondria of stem cells during embryonic stages could uncover mitochondrial adaptability on cellular demands. Moreover, investigating the importance of mitochondria in pluripotency maintenance might unravel the cause of mitochondrial diseases, aging, and regenerative therapies.