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Cited by 173Mitochondrial Function and PathologyMetabolism, Diabetes, and CancerBiochemical Acid Research Studies

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The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

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Zangari, Joséphine, Petrelli, Francesco, Maillot, Benoît, Martinou, Jean-Claude·2020·Biomolecules
DOI 10.3390/biom10071068PMC PMC7407832
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Abstract

Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the recently identified mitochondrial pyruvate carrier (MPC). In this review, we report the latest findings on the physiology of the MPC and we discuss how a dysfunctional MPC can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, and cancer.

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Figure 1 Metabolic pathways involving mitochondria. In the cytosol, pyruvate is produced through glycolysis, which generates two adenosine triphosphate (ATP) and two reduced nicotinamide adenine dinucleotide (NADH) molecules per molecule of glucose. Pyruvate can also be produced from oxidation of lactate by lactate dehydrogenase (LDH), conversion from alanine by alanine transaminase (ALT), or from malate by cytosolic or mitochondrial malic enzyme (ME). Pyruvate can be imported into mitochondria to be oxidized into acetyl coenzyme A (acetyl-CoA) by the pyruvate dehydrogenase (PDH), which then fuels the tricarboxylic acid (TCA) cycle. Import of pyruvate requires the voltage-dependent anion channel (VDAC) to cross the outer mitochondrial membrane (OMM) and the mitochondrial pyruvate carrier (MPC) to cross the inner mitochondrial membrane (IMM). The TCA cycle can also be fueled by glutamine (Gln) through glutaminolysis or by fatty acids (FA) released from lipid droplets (LD) where they are stored in the form of triglycerides (TG). FAs provide acetyl-CoA through FA β-oxidation. The TCA cycle and β-oxidation both generate the reducing equivalents NADH and flavin adenine dinucleotide (FADH2), which transfer electrons to the electron respiratory chain (ETC), generating more than 30 ATP molecules per molecule of glucose. The last reaction is catalyzed by ATP synthase or Complex V (CV). This process requires the presence of oxygen and is known as oxidative phosphorylation (OXPHOS). In the liver and kidney, pyruvate can be converted into oxaloacetate (OAA) by the pyruvate carboxylase (PC), which is then reduced into malate by the malate dehydrogenase (mMDH). Malate is then exported into the cytosol, converted into OAA by malate dehydrogenase (cMDH) and into phosphoenolpyruvate (PEP) by PEP carboxykinase (PEPCK) and from there into glucose through several steps, including the reversible steps of glycolysis. IMS: intermembrane space; CPT1: carnitine palmitoyltransferase 1; CPT2: carnitine palmitoyltransferase 2; GDH: glutamate dehydrogenase; GLS: glutamase; α-KG: α-ketoglutarate.
Figure 1 Metabolic pathways involving mitochondria. In the cytosol, pyruvate is produced through glycolysis, which generates two adenosine triphosphate (ATP) and two reduced nicotinamide adenine dinucleotide (NADH) molecules per molecule of glucose. Pyruvate can also be produced from oxidation of lactate by lactate dehydrogenase (LDH), conversion from alanine by alanine transaminase (ALT), or from malate by cytosolic or mitochondrial malic enzyme (ME). Pyruvate can be imported into mitochondria to be oxidized into acetyl coenzyme A (acetyl-CoA) by the pyruvate dehydrogenase (PDH), which then fuels the tricarboxylic acid (TCA) cycle. Import of pyruvate requires the voltage-dependent anion channel (VDAC) to cross the outer mitochondrial membrane (OMM) and the mitochondrial pyruvate carrier (MPC) to cross the inner mitochondrial membrane (IMM). The TCA cycle can also be fueled by glutamine (Gln) through glutaminolysis or by fatty acids (FA) released from lipid droplets (LD) where they are stored in the form of triglycerides (TG). FAs provide acetyl-CoA through FA β-oxidation. The TCA cycle and β-oxidation both generate the reducing equivalents NADH and flavin adenine dinucleotide (FADH2), which transfer electrons to the electron respiratory chain (ETC), generating more than 30 ATP molecules per molecule of glucose. The last reaction is catalyzed by ATP synthase or Complex V (CV). This process requires the presence of oxygen and is known as oxidative phosphorylation (OXPHOS). In the liver and kidney, pyruvate can be converted into oxaloacetate (OAA) by the pyruvate carboxylase (PC), which is then reduced into malate by the malate dehydrogenase (mMDH). Malate is then exported into the cytosol, converted into OAA by malate dehydrogenase (cMDH) and into phosphoenolpyruvate (PEP) by PEP carboxykinase (PEPCK) and from there into glucose through several steps, including the reversible steps of glycolysis. IMS: intermembrane space; CPT1: carnitine palmitoyltransferase 1; CPT2: carnitine palmitoyltransferase 2; GDH: glutamate dehydrogenase; GLS: glutamase; α-KG: α-ketoglutarate.CC BY · PubMed Central
Figure 2 (A) Semi-SWEET and SWEET motifs. Semi-SWEET is composed of a triple helix bundle in this specific order 1-3-2. SWEET contains two semi-SWEET motifs linked together by a helix. All the helices are crossing the membrane. (B) Model for the topology of MPC1 and MPC2 in the inner mitochondrial membrane (IMM). Here, a semi-SWEET structure is proposed for both MPC1 and MPC2. MA: matrix; IMS: intermembrane space.
Figure 2 (A) Semi-SWEET and SWEET motifs. Semi-SWEET is composed of a triple helix bundle in this specific order 1-3-2. SWEET contains two semi-SWEET motifs linked together by a helix. All the helices are crossing the membrane. (B) Model for the topology of MPC1 and MPC2 in the inner mitochondrial membrane (IMM). Here, a semi-SWEET structure is proposed for both MPC1 and MPC2. MA: matrix; IMS: intermembrane space.CC BY · PubMed Central
Figure 3 Tumor cell metabolism. In the primary tumor site, cancer cells mainly rely on aerobic glycolysis (Warburg effect) and this metabolism favors cell proliferation and tumor growth. Some cancer cells escape from the primary tumor site through the bloodstream, generating metastasis in other organs. It is thought that, to do this, some cancer cell types switch to a more oxidative metabolism.
Figure 3 Tumor cell metabolism. In the primary tumor site, cancer cells mainly rely on aerobic glycolysis (Warburg effect) and this metabolism favors cell proliferation and tumor growth. Some cancer cells escape from the primary tumor site through the bloodstream, generating metastasis in other organs. It is thought that, to do this, some cancer cell types switch to a more oxidative metabolism.CC BY · PubMed Central

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Metadata

Authors
Zangari, J., Petrelli, F., Maillot, B., & Martinou, J.-C.
Affiliations
University of Geneva (CH)
Corresponding author
Martinou, Jean-Claude
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2020-07-17
Volume
10
Issue
7
Pages
1068
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom10071068
PMC
PMC7407832
OpenAlex
W3042494222
Cited by
172
References
103
Citations by year
2026: 33 · 2025: 47 · 2024: 33 · 2023: 30 · 2022: 16 · 2021: 11 · 2020: 2
FWCI
1.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Oncosuisse (KFS-4434-02-2018)
  • Swiss National Foundation (31003A_179421)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
Keywords
pyruvate metabolism, mitochondrial pyruvate carrier, glycolysis, TCA cycle, oxidative phosphorylation, mitochondrial dysfunction, neurodegenerative diseases, metabolic disorders, cancer
MeSH terms
Animals, Gene Expression Regulation, Humans, Metabolic Diseases, Mitochondria, Neoplasms, Pyruvic Acid, Neurodegenerative Diseases, Monocarboxylic Acid Transporters, Mitochondrial Membrane Transport Proteins

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