Mitochondrial pyruvate carrier as a key regulator of fever and neuroinflammation

Guimarães, Natália Carvalho; Alves, D.; Vilela, Wembley Rodrigues; de‐Souza‐Ferreira, Eduardo; Gomes, Bruna Rafaela Bezerra; Ott, Daniela; Murgott, Jolanta; Souza, Paulo Eduardo Narcizo de; Sousa, Marcelo Valle de; Galina, Antônio; Roth, Joachim; de, Andreza Fabro; Veiga-Souza, Fabiane H.

doi:10.1016/j.bbi.2020.11.031

Cited by 11 publications

(4 citation statements)

References 70 publications

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“…28 MPC is widely distributed in the human body including the CNS, such as the thalamus, hippocampus, cerebral cortex, and dopaminergic neurons. 29 In experimental models of degenerative diseases, the pyruvate transport restriction by inhibiting MPC attenuates inflammatory response and enhanced neuroprotection. 30 Thiazolidinediones (TZDs), including pyrrolidone and rosiglitazone, are commonly used antidiabetic drugs and are also a class of MPC inhibitors.…”

Section: Central Nervous System Degenerative Diseasesmentioning

confidence: 99%

Recent Advances in Mitochondrial Pyruvate Carrier Inhibitors

Huang,

Zhang,

Peng

et al. 2024

Pharmaceutical Fronts

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The mitochondrial pyruvate carrier (MPC) exists in the mitochondria inner membrane which transports pyruvate to the mitochondrial matrix. Evidence shows that MPC is the breakthrough point to study the regulation of basic energy metabolism, the dysfunction of which may lead to metabolic disturbance. Due to its important metabolic function, MPC has been considered a potential therapeutic target for diabetes, alopecia, cancers, neurodegenerative diseases, and liver metabolic diseases. However, MPC' protein crystal structure is still not clear as the proteins involved were only identified 10 years ago, making it difficult to carry out rational drug design based on receptor structure. In this review, we summarize the latest applications of MPC in different diseases and discuss the recent advances in pharmacochemical strategies of small-molecule inhibitors of MPC, hoping to promote the development of specific MPC inhibitors.

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Section: Central Nervous System Degenerative Diseasesmentioning

confidence: 99%

Recent Advances in Mitochondrial Pyruvate Carrier Inhibitors

Huang,

Zhang,

Peng

et al. 2024

Pharmaceutical Fronts

View full text Add to dashboard Cite

show abstract

“…The crude 30-day mortality was 48% for those with a temperature <35° C and 11% for those with a temperature >41° C [15]. Functioning mitochondria prioritising uncoupled respiration over ATP production are necessary to produce fever [16] and inhibition of mitochondrial function by inhibition of the mitochondrial pyruvate carrier (MPC) prevents fever [17].…”

Section: The Hypo Inflammatory Phase Of Sepsismentioning

confidence: 99%

<strong></strong>Thiamine and High Dose Insulin Treatment for Sepsis<strong> </strong>

Bradley¹

2023

Preprint

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Sepsis is a major health problem and accounts for 20 per cent of deaths worldwide. It is the most expensive condition treated in United States hospitals at $27 billion per year or about $20,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only marginal impact. Mortality is about 27 per cent for hospitalized patients and about 42 per cent for patients in intensive care.There are two phases of sepsis – a hyper inflammatory phase and a subsequent hypo inflammatory phase.During the hyper inflammatory phase the metabolic rate increases associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and migration of those leucocytes to infected and damaged tissues and an increased supply and consumption of glucose to fuel this immune system.During the subsequent hypo inflammatory phase the metabolic rate declines and this is associated with a decrease in body temperature and a generalized decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life threatening circumstances. Thus adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened then mitochondrial production of ATP is partially or substantially suppressed in favor of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischemic, or damaged tissues.However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery.It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients leading to a substantial ATP deficit. This is the fundamental issue of sepsis.This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyper glycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypo metabolic (hypo inflammatory) phase of sepsis should significantly improve survival.

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“…The crude 30-day mortality was 48% for those with a temperature < 35°C and 11% for those with a temperature > 41°C [15]. Functioning mitochondria prioritising uncoupled respiration over ATP production are necessary to produce fever [16], and inhibition of mitochondrial function by inhibition of the mitochondrial pyruvate carrier prevents fever [17].…”

Section: The Hypoinflammatory Phase Of Sepsismentioning

confidence: 99%

Thiamine and High Dose Insulin Treatment for Sepsis

Bradley

2023

CAJMHE

View full text Add to dashboard Cite

Sepsis is a major health problem and accounts for 20% of deaths worldwide. It is the most expensive condition treated in United States hospitals at $62 billion per year or about $46,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only a marginal impact. Mortality is about 27% for hospitalised patients and about 42% for patients in intensive care. There are two phases of sepsis – a hyperinflammatory phase and a subsequent hypoinflammatory phase. During the hyperinflammatory phase, the metabolic rate increases, and this is associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and their migration to infected and damaged tissues and increased supply and consumption of glucose to fuel this immune system. During the subsequent hypoinflammatory phase, the metabolic rate decreases, and this is associated with a decrease in body temperature and a generalised decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life-threatening circumstances. Thus, adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened, then the mitochondrial production of ATP is partially or substantially suppressed in favour of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischaemic, or damaged tissues. However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery. It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients, leading to a substantial ATP deficit. This is the fundamental issue of sepsis. This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyperglycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypometabolic (hypoinflammatory) phase of sepsis, may enhance survival relative to thiamine alone.

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Mitochondrial pyruvate carrier as a key regulator of fever and neuroinflammation

Cited by 11 publications

References 70 publications

Recent Advances in Mitochondrial Pyruvate Carrier Inhibitors

Recent Advances in Mitochondrial Pyruvate Carrier Inhibitors

<strong></strong>Thiamine and High Dose Insulin Treatment for Sepsis<strong> </strong>

Thiamine and High Dose Insulin Treatment for Sepsis

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