- Email: [email protected]
Obesity Protects Cancer from Drugs Targeting Blood Vessels
Cell Metabolism
Previews Obesity Protects Cancer from Drugs Targeting Blood Vessels Yihai Cao1,* 1Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.05.014
Drugs that target angiogenesis are commonly used for treating various cancers, but their clinical benefits are limited. In a recent Science Translational Medicine article, Incio et al. (2018) provide mechanistic insight on the role of obesity in the development of anti-VEGF drug resistance in human patients and murine models of breast cancer. Obesity is one of the most important public health problems and a major driver of preventable chronic diseases including cardiovascular disease, stroke, type 2 diabetes, and certain types of cancer. According to the World Health Organization (WHO, 2014), around 2 billion adults of the global population are overweight and 670 million are defined as obese (BMI R 30 kg/m2). Several published studies show that overweight and obesity are associated with high incidences of many cancer types, including endometrial, esophageal, gastric, liver, pancreatic, colorectal, thyroid, ovarian, and breast (BC) (Arnold et al., 2015; Renehan et al., 2008). A population-based study indicates a 20%–40% increase of BC incidence in postmenopausal obese women relative to lean women (Munsell et al., 2014). In fact, the majority of BC patients are overweight or obese at diagnosis (Sparano et al., 2012). The concept of antiangiogenic therapy was originally proposed by Judah Folkman nearly a half-century ago (Folkman, 1971). Today, antiangiogenic drugs (AADs) are widely used for treating various types of human cancers and have become one of the most important therapeutic modalities (Cao et al., 2011). Most clinically available AADs are designed for blocking the VEGF-VEGFR signaling pathway, which is commonly utilized by tumors to grow new vessels (Cao, 2014). Despite their clinical success of cancer treatment, AADs in most cases used either alone or in combination with other therapeutics produce only limited survival benefits in human cancer patients. In metastatic BC, the US-FDA withdrew the previously approved bevacizumab owing to lack of overt survival benefit (D’Agostino, 2011).
Among many unresolved issues in the effort of improving therapeutic benefits, overcoming AAD resistance is the most crucial task in improving therapeutic efficacy for BC and other cancer patients. Unfortunately, mechanisms that underlie AAD resistance are not fully understood. In particular, the relation between obesity and anti-VEGF response is an overlooked area. In their recent published article, Incio et al. address the relationship between obesity and the anti-VEGF response using both clinical BC patient materials and preclinical BC animal models (Incio et al., 2018). In a phase II clinical trial, they have found that tumor masses are significantly larger in the BMI R 25.0 group versus those with BMI < 25.0. Interestingly, tumor vessel density inversely correlates with the adipose area prior to the anti-VEGF treatment. BC tumors containing larger adipose areas suffer from hypoxia due to hypo-vascularization. After 2 weeks of anti-VEGF treatment, tumor vessel density and hypoxia become indistinguishable in lean and obese patients owing to hypersensitivity of tumors in lean patients in response to anti-VEGF therapy. These clinical data demonstrate that tumor vessels in obese patients are intrinsically resistant to anti-VEGF therapy. Of note, increased levels of circulating IL-6 and FGF-2 are present in these obese patients. In mouse BC models, at the initial stage of cancer development, the authors find that tumors grow faster in obese mice compared to their counterpart lean mice (Figures 1A and 1B). However, it is unclear why tumors grow faster in the presence of low vessel density and hypoxia. In sizematched tumors, anti-VEGF treatment
produces greater anti-tumor effects in lean mice relative to obese mice. AntiVEGF treatment produces >50% tumor inhibition in lean animals, whereas less than 28% tumor inhibition is seen in obese mice. By switching the mice from a lowfat to a high-fat diet, the authors exclude the impact of nutrients on tumor growth and conclude that body weight is the key factor affecting tumor growth and drug response. Consistent with findings from human tumors, BC tumor tissues from obese mice contain a low density of vessels and suffer from hypoxia. Several cell-proliferation-related signaling molecules, including ERK, AKT, and S6, are persistently expressed at high levels even in the presence of anti-VEGF drugs. Tumor cell proliferation and poor antiVEGF response are correlated with adipose contents. An interesting notion in both human and mouse tumor samples is the existence of tumor hypovascularity and hypoxia, particularly in the tumor area adjacent to adipocytes in obesity. Perhaps the enlarged adipocyte size in obese individuals is partly responsible for causing hypoxia. One explanation would be that enlargement of adipocyte sizes would increase inter-capillary distance between tumor cells and microvessels and subsequently decrease oxygen diffusion. IL-6 production significantly increases in the adipocyte-rich region that is often hypoxic. To investigate the functional impact of IL-6 on developing anti-VEGF resistance, both pharmacological and genetic lossof-function approaches are employed in this study. Incio et al. (2018) discover that blocking IL-6 restores the anti-VEGF sensitivity of tumor suppression in obese mice. In another mouse BC tumor model,
Cell Metabolism 27, June 5, 2018 ª 2018 Elsevier Inc. 1163
Cell Metabolism
Previews A
B
Figure 1. Differential Anti-VEGF Drug Responses of Breast Cancer in Lean and Obese Individuals (A) In breast cancers (BCs) growing in lean individuals, tumor cells (TC) and other stromal cells in the tumor microenvironment, including tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), and adipocytes (AC), produce high levels of VEGF, which stimulates tumor angiogenesis and vascular survival. Blocking VEGF by a neutralizing antibody such as bevacizumab decreases tumor vascularity and inhibits tumor growth. Thus, treatment of VEGFdependent tumor angiogenesis by VEGF blockade is likely beneficial in lean patients with BC. (B) BCs cancers adjacent to obese adipose tissues produce high levels of IL-6 or FGF-2 owing to hypoxia. Both IL-6 and FGF-2 promote tumor growth through multiple mechanisms, including their direct effects on tumor cells, recruiting inflammatory cells, and stimulating angiogenesis. These factors are not targets of anti-VEGF drugs. Treating these obese adipose-tissue-associated BCs with anti-VEGF drugs would produce minimal or no therapeutic benefits, owing to a compensatory resistance mechanism circumventing the drug’s original targets.
they find that FGF-2, but not IL-6, contributes to anti-VEGF resistance and that inhibition of the FGF-2-FGFR signaling improves anti-VEGF responses. Together with other published findings, this study supports an emerging compensatory mechanism of anti-VEGF resistance. There are several important issues that warrant further investigation. Would the IL-6- and FGF-2-mediated anti-VEGF-resistant mechanism also exist in other cancers? Are there more molecular players other than IL-6 and FGF-2 in mediating anti-VEGF resistance in BC and other cancers? If so, how do we translate this information into clinical practice? Should we profile gene expression of all growth factors and cytokines in every cancer patient prior to initiating antiangiogenic therapy? When 1164 Cell Metabolism 27, June 5, 2018
so many factors are co-present in the same tumor microenvironment, how do we deal with their synergistic effects? Even though the expression level of X factor is not necessarily high, its synergistic effect with another modestly expressed factor Y could augment a robust angiogenic response. If combination therapy is more effective, how many different drugs should be combined for effectively treating a cancer patient? Clinical results from combination therapies have demonstrated that not all combinations produce the expected beneficial effects in cancer patients. In contrast, adding drug compositions in a combinatorial fashion often increases adverse effects. This and other studies show that hypoxia is a key driving force for anti-VEGF
resistance. If hypoxia exists in BC tumors grown in obese individuals prior to treatment, these tumors should become intrinsically resistant to anti-VEGF therapy through the mechanisms uncovered in this study. Another interesting issue is the relationship between anti-VEGF treatment and tumor hypoxia. This is a highly debatable issue. While some findings claim that anti-VEGF therapy induces tumor hypoxia by regressing the microvasculature, other studies demonstrate that anti-VEGF-induced vascular normalization improves tumor hypoxia by increasing vascular perfusion. At the time of writing, this controversial issue has not been resolved. Perhaps various tumors respond differently to anti-VEGF therapy. If anti-VEGF augments tumor hypoxia, it suggests that anti-VEGF drugs
Cell Metabolism
Previews might trigger evasive drug resistance through the hypoxia-induced IL-6 and FGF-2. The hypoxia-triggered antiVEGF-resistant mechanism has been proposed by other studies (Bergers and Hanahan, 2008). In addition to producing IL-6 and FGF-2, adipocytes also produce a broad array of adipokines that stimulate angiogenesis. It would be interesting for future studies to investigate the functional roles of adipokines in developing ADD resistance. Of course, one study would not be able to address all questions. This exciting study has mechanistically linked two major health problems—obesity and cancer—in a drug response. For the obese population diagnosed with cancer, patients not only have poor prognosis but also respond poorly to cancer drugs. Together with other findings, this work also supports the notion of accelerated BC tumor growth rates in obese animals. Along this line, an extended explanation for the accelerated tumor growth rate would be that adipocytes might also provide energy fuel for tumor mass
expansion. From this study and others, we are reminded of the benefits of remaining lean—not only for our general health but also for the benefits of AADs in the face of cancer.
Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186. Incio, J., Ligibel, J.A., McManus, D.T., Suboj, P., Jung, K., Kawaguchi, K., Pinter, M., Babykutty, S., Chin, S.M., Vardam, T.D., et al. (2018). Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci. Transl. Med. 10, eaag0945.
REFERENCES Arnold, M., Pandeya, N., Byrnes, G., Renehan, P.A.G., Stevens, G.A., Ezzati, P.M., Ferlay, J., Miranda, J.J., Romieu, I., Dikshit, R., et al. (2015). Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 16, 36–46. Bergers, G., and Hanahan, D. (2008). Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603. Cao, Y. (2014). VEGF-targeted cancer therapeutics-paradoxical effects in endocrine organs. Nat. Rev. Endocrinol. 10, 530–539. Cao, Y., Arbiser, J., D’Amato, R.J., D’Amore, P.A., Ingber, D.E., Kerbel, R., Klagsbrun, M., Lim, S., Moses, M.A., Zetter, B., et al. (2011). Forty-year journey of angiogenesis translational research. Sci. Transl. Med. 3, 114rv3. D’Agostino, R.B., Sr. (2011). Changing end points in breast-cancer drug approval–the Avastin story. N. Engl. J. Med. 365, e2.
Munsell, M.F., Sprague, B.L., Berry, D.A., Chisholm, G., and Trentham-Dietz, A. (2014). Body mass index and breast cancer risk according to postmenopausal estrogen-progestin use and hormone receptor status. Epidemiol. Rev. 36, 114–136. Renehan, A.G., Tyson, M., Egger, M., Heller, R.F., and Zwahlen, M. (2008). Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578. Sparano, J.A., Wang, M., Zhao, F., Stearns, V., Martino, S., Ligibel, J.A., Perez, E.A., Saphner, T., Wolff, A.C., Sledge, G.W., Jr., et al. (2012). Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer. Cancer 118, 5937–5946. World Health Organization (WHO) (2014). Global status report on noncommunicable diseases 2014. http://www.who.int/nmh/publications/ncdstatus-report-2014/en/.
OXPHOS Defects Due to mtDNA Mutations: Glutamine to the Rescue! Christos Chinopoulos1,* 1Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.05.010
Mutations in mtDNA associated with OXPHOS defects preclude energy harnessing by OXPHOS. The work of Chen et al. (2018) is previewed, reporting flux pathways of glutamine catabolism in mtDNA mutant cells yielding high-energy phosphates through substrate-level phosphorylation and the influence exerted by the severity of OXPHOS impairment.
Mitochondrial diseases manifesting severe neurological and myopathic phenotypes due to mtDNA mutations are often associated with oxidative phosphorylation (OXPHOS) defects. Under these circumstances, provision of high-energy phosphates by the Fo-F1 ATP synthase is impossible. To this end, the only means for obtaining ATP in the matrix is through
mitochondrial substrate-level phosphorylation (mSLP) substantiated by succinateCoA ligase, which does not depend on oxygen or glucose. Furthermore, provision of ATP by mSLP in the matrix is important not only as a mere means of energy, but also to prevent mitochondria from straining glycolytic ATP reserves by maintaining the adenine nucleotide
translocase in ‘‘forward mode’’ carrying ATP toward the cytosol (Chinopoulos et al., 2010). Several metabolites converge to mSLP, but catabolism of glutamine powering the oxidative flux of a-ketoglutarate (aKg) toward ketoglutarate dehydrogenase complex (KGDHC) and succinate-CoA ligase takes the lion’s share (Altman et al.,
Cell Metabolism 27, June 5, 2018 ª 2018 Elsevier Inc. 1165
Previews Obesity Protects Cancer from Drugs Targeting Blood Vessels Yihai Cao1,* 1Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.05.014
Drugs that target angiogenesis are commonly used for treating various cancers, but their clinical benefits are limited. In a recent Science Translational Medicine article, Incio et al. (2018) provide mechanistic insight on the role of obesity in the development of anti-VEGF drug resistance in human patients and murine models of breast cancer. Obesity is one of the most important public health problems and a major driver of preventable chronic diseases including cardiovascular disease, stroke, type 2 diabetes, and certain types of cancer. According to the World Health Organization (WHO, 2014), around 2 billion adults of the global population are overweight and 670 million are defined as obese (BMI R 30 kg/m2). Several published studies show that overweight and obesity are associated with high incidences of many cancer types, including endometrial, esophageal, gastric, liver, pancreatic, colorectal, thyroid, ovarian, and breast (BC) (Arnold et al., 2015; Renehan et al., 2008). A population-based study indicates a 20%–40% increase of BC incidence in postmenopausal obese women relative to lean women (Munsell et al., 2014). In fact, the majority of BC patients are overweight or obese at diagnosis (Sparano et al., 2012). The concept of antiangiogenic therapy was originally proposed by Judah Folkman nearly a half-century ago (Folkman, 1971). Today, antiangiogenic drugs (AADs) are widely used for treating various types of human cancers and have become one of the most important therapeutic modalities (Cao et al., 2011). Most clinically available AADs are designed for blocking the VEGF-VEGFR signaling pathway, which is commonly utilized by tumors to grow new vessels (Cao, 2014). Despite their clinical success of cancer treatment, AADs in most cases used either alone or in combination with other therapeutics produce only limited survival benefits in human cancer patients. In metastatic BC, the US-FDA withdrew the previously approved bevacizumab owing to lack of overt survival benefit (D’Agostino, 2011).
Among many unresolved issues in the effort of improving therapeutic benefits, overcoming AAD resistance is the most crucial task in improving therapeutic efficacy for BC and other cancer patients. Unfortunately, mechanisms that underlie AAD resistance are not fully understood. In particular, the relation between obesity and anti-VEGF response is an overlooked area. In their recent published article, Incio et al. address the relationship between obesity and the anti-VEGF response using both clinical BC patient materials and preclinical BC animal models (Incio et al., 2018). In a phase II clinical trial, they have found that tumor masses are significantly larger in the BMI R 25.0 group versus those with BMI < 25.0. Interestingly, tumor vessel density inversely correlates with the adipose area prior to the anti-VEGF treatment. BC tumors containing larger adipose areas suffer from hypoxia due to hypo-vascularization. After 2 weeks of anti-VEGF treatment, tumor vessel density and hypoxia become indistinguishable in lean and obese patients owing to hypersensitivity of tumors in lean patients in response to anti-VEGF therapy. These clinical data demonstrate that tumor vessels in obese patients are intrinsically resistant to anti-VEGF therapy. Of note, increased levels of circulating IL-6 and FGF-2 are present in these obese patients. In mouse BC models, at the initial stage of cancer development, the authors find that tumors grow faster in obese mice compared to their counterpart lean mice (Figures 1A and 1B). However, it is unclear why tumors grow faster in the presence of low vessel density and hypoxia. In sizematched tumors, anti-VEGF treatment
produces greater anti-tumor effects in lean mice relative to obese mice. AntiVEGF treatment produces >50% tumor inhibition in lean animals, whereas less than 28% tumor inhibition is seen in obese mice. By switching the mice from a lowfat to a high-fat diet, the authors exclude the impact of nutrients on tumor growth and conclude that body weight is the key factor affecting tumor growth and drug response. Consistent with findings from human tumors, BC tumor tissues from obese mice contain a low density of vessels and suffer from hypoxia. Several cell-proliferation-related signaling molecules, including ERK, AKT, and S6, are persistently expressed at high levels even in the presence of anti-VEGF drugs. Tumor cell proliferation and poor antiVEGF response are correlated with adipose contents. An interesting notion in both human and mouse tumor samples is the existence of tumor hypovascularity and hypoxia, particularly in the tumor area adjacent to adipocytes in obesity. Perhaps the enlarged adipocyte size in obese individuals is partly responsible for causing hypoxia. One explanation would be that enlargement of adipocyte sizes would increase inter-capillary distance between tumor cells and microvessels and subsequently decrease oxygen diffusion. IL-6 production significantly increases in the adipocyte-rich region that is often hypoxic. To investigate the functional impact of IL-6 on developing anti-VEGF resistance, both pharmacological and genetic lossof-function approaches are employed in this study. Incio et al. (2018) discover that blocking IL-6 restores the anti-VEGF sensitivity of tumor suppression in obese mice. In another mouse BC tumor model,
Cell Metabolism 27, June 5, 2018 ª 2018 Elsevier Inc. 1163
Cell Metabolism
Previews A
B
Figure 1. Differential Anti-VEGF Drug Responses of Breast Cancer in Lean and Obese Individuals (A) In breast cancers (BCs) growing in lean individuals, tumor cells (TC) and other stromal cells in the tumor microenvironment, including tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), and adipocytes (AC), produce high levels of VEGF, which stimulates tumor angiogenesis and vascular survival. Blocking VEGF by a neutralizing antibody such as bevacizumab decreases tumor vascularity and inhibits tumor growth. Thus, treatment of VEGFdependent tumor angiogenesis by VEGF blockade is likely beneficial in lean patients with BC. (B) BCs cancers adjacent to obese adipose tissues produce high levels of IL-6 or FGF-2 owing to hypoxia. Both IL-6 and FGF-2 promote tumor growth through multiple mechanisms, including their direct effects on tumor cells, recruiting inflammatory cells, and stimulating angiogenesis. These factors are not targets of anti-VEGF drugs. Treating these obese adipose-tissue-associated BCs with anti-VEGF drugs would produce minimal or no therapeutic benefits, owing to a compensatory resistance mechanism circumventing the drug’s original targets.
they find that FGF-2, but not IL-6, contributes to anti-VEGF resistance and that inhibition of the FGF-2-FGFR signaling improves anti-VEGF responses. Together with other published findings, this study supports an emerging compensatory mechanism of anti-VEGF resistance. There are several important issues that warrant further investigation. Would the IL-6- and FGF-2-mediated anti-VEGF-resistant mechanism also exist in other cancers? Are there more molecular players other than IL-6 and FGF-2 in mediating anti-VEGF resistance in BC and other cancers? If so, how do we translate this information into clinical practice? Should we profile gene expression of all growth factors and cytokines in every cancer patient prior to initiating antiangiogenic therapy? When 1164 Cell Metabolism 27, June 5, 2018
so many factors are co-present in the same tumor microenvironment, how do we deal with their synergistic effects? Even though the expression level of X factor is not necessarily high, its synergistic effect with another modestly expressed factor Y could augment a robust angiogenic response. If combination therapy is more effective, how many different drugs should be combined for effectively treating a cancer patient? Clinical results from combination therapies have demonstrated that not all combinations produce the expected beneficial effects in cancer patients. In contrast, adding drug compositions in a combinatorial fashion often increases adverse effects. This and other studies show that hypoxia is a key driving force for anti-VEGF
resistance. If hypoxia exists in BC tumors grown in obese individuals prior to treatment, these tumors should become intrinsically resistant to anti-VEGF therapy through the mechanisms uncovered in this study. Another interesting issue is the relationship between anti-VEGF treatment and tumor hypoxia. This is a highly debatable issue. While some findings claim that anti-VEGF therapy induces tumor hypoxia by regressing the microvasculature, other studies demonstrate that anti-VEGF-induced vascular normalization improves tumor hypoxia by increasing vascular perfusion. At the time of writing, this controversial issue has not been resolved. Perhaps various tumors respond differently to anti-VEGF therapy. If anti-VEGF augments tumor hypoxia, it suggests that anti-VEGF drugs
Cell Metabolism
Previews might trigger evasive drug resistance through the hypoxia-induced IL-6 and FGF-2. The hypoxia-triggered antiVEGF-resistant mechanism has been proposed by other studies (Bergers and Hanahan, 2008). In addition to producing IL-6 and FGF-2, adipocytes also produce a broad array of adipokines that stimulate angiogenesis. It would be interesting for future studies to investigate the functional roles of adipokines in developing ADD resistance. Of course, one study would not be able to address all questions. This exciting study has mechanistically linked two major health problems—obesity and cancer—in a drug response. For the obese population diagnosed with cancer, patients not only have poor prognosis but also respond poorly to cancer drugs. Together with other findings, this work also supports the notion of accelerated BC tumor growth rates in obese animals. Along this line, an extended explanation for the accelerated tumor growth rate would be that adipocytes might also provide energy fuel for tumor mass
expansion. From this study and others, we are reminded of the benefits of remaining lean—not only for our general health but also for the benefits of AADs in the face of cancer.
Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186. Incio, J., Ligibel, J.A., McManus, D.T., Suboj, P., Jung, K., Kawaguchi, K., Pinter, M., Babykutty, S., Chin, S.M., Vardam, T.D., et al. (2018). Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Sci. Transl. Med. 10, eaag0945.
REFERENCES Arnold, M., Pandeya, N., Byrnes, G., Renehan, P.A.G., Stevens, G.A., Ezzati, P.M., Ferlay, J., Miranda, J.J., Romieu, I., Dikshit, R., et al. (2015). Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 16, 36–46. Bergers, G., and Hanahan, D. (2008). Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592–603. Cao, Y. (2014). VEGF-targeted cancer therapeutics-paradoxical effects in endocrine organs. Nat. Rev. Endocrinol. 10, 530–539. Cao, Y., Arbiser, J., D’Amato, R.J., D’Amore, P.A., Ingber, D.E., Kerbel, R., Klagsbrun, M., Lim, S., Moses, M.A., Zetter, B., et al. (2011). Forty-year journey of angiogenesis translational research. Sci. Transl. Med. 3, 114rv3. D’Agostino, R.B., Sr. (2011). Changing end points in breast-cancer drug approval–the Avastin story. N. Engl. J. Med. 365, e2.
Munsell, M.F., Sprague, B.L., Berry, D.A., Chisholm, G., and Trentham-Dietz, A. (2014). Body mass index and breast cancer risk according to postmenopausal estrogen-progestin use and hormone receptor status. Epidemiol. Rev. 36, 114–136. Renehan, A.G., Tyson, M., Egger, M., Heller, R.F., and Zwahlen, M. (2008). Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578. Sparano, J.A., Wang, M., Zhao, F., Stearns, V., Martino, S., Ligibel, J.A., Perez, E.A., Saphner, T., Wolff, A.C., Sledge, G.W., Jr., et al. (2012). Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer. Cancer 118, 5937–5946. World Health Organization (WHO) (2014). Global status report on noncommunicable diseases 2014. http://www.who.int/nmh/publications/ncdstatus-report-2014/en/.
OXPHOS Defects Due to mtDNA Mutations: Glutamine to the Rescue! Christos Chinopoulos1,* 1Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2018.05.010
Mutations in mtDNA associated with OXPHOS defects preclude energy harnessing by OXPHOS. The work of Chen et al. (2018) is previewed, reporting flux pathways of glutamine catabolism in mtDNA mutant cells yielding high-energy phosphates through substrate-level phosphorylation and the influence exerted by the severity of OXPHOS impairment.
Mitochondrial diseases manifesting severe neurological and myopathic phenotypes due to mtDNA mutations are often associated with oxidative phosphorylation (OXPHOS) defects. Under these circumstances, provision of high-energy phosphates by the Fo-F1 ATP synthase is impossible. To this end, the only means for obtaining ATP in the matrix is through
mitochondrial substrate-level phosphorylation (mSLP) substantiated by succinateCoA ligase, which does not depend on oxygen or glucose. Furthermore, provision of ATP by mSLP in the matrix is important not only as a mere means of energy, but also to prevent mitochondria from straining glycolytic ATP reserves by maintaining the adenine nucleotide
translocase in ‘‘forward mode’’ carrying ATP toward the cytosol (Chinopoulos et al., 2010). Several metabolites converge to mSLP, but catabolism of glutamine powering the oxidative flux of a-ketoglutarate (aKg) toward ketoglutarate dehydrogenase complex (KGDHC) and succinate-CoA ligase takes the lion’s share (Altman et al.,
Cell Metabolism 27, June 5, 2018 ª 2018 Elsevier Inc. 1165