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Including the mitochondrial metabolism of l-lactate in cancer metabolic reprogramming

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Abstract

Glucose avidity, high glycolysis and l-lactate production, regardless of oxygen availability, are the main traits of cancer metabolic reprogramming. The idea that mitochondria are dysfunctional in cancer, thus causing a glycolysis increase for ATP production and l-lactate accumulation as a dead-end product of glucose catabolism, has oriented cancer research for many years. However, it was shown that mitochondrial metabolism is essential for cancer cell proliferation and tumorigenesis and that l-lactate is a fundamental energy substrate with tumor growth-promoting and signaling capabilities. Nevertheless, the known ability of mitochondria to take up and oxidize l-lactate has remained ignored by cancer research. Beginning with a brief overview of the metabolic changes occurring in cancer, we review the present knowledge of l-lactate formation, transport, and intracellular oxidation and underline the possible role of l-lactate metabolism as energetic, signaling and anabolic support for cancer cell proliferation. These unexplored aspects of cancer biochemistry might be exploited for therapeutic benefit.

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Abbreviations

F2,6BP:

Fructose-2,6-bisphosphate

GLN:

Glutamine

GLU:

Glucose

GLUT:

Glucose transporter

G6P:

Glucose-6-phosphate

HK:

Hexokinase

l-LAC:

l-Lactate

l-LDHA:

l-Lactate dehydrogenase A

cl-LDH:

Cytosolic l-lactate dehydrogenase

ml-LDH:

Mitochondrial l-lactate dehydrogenase

MCT:

Monocarboxylate carrier

MIM:

Mitochondrial inner membrane

MOM:

Mitochondrial outer membrane

MPC:

Mitochondrial pyruvate carrier

mRC:

Mitochondrial respiratory chain

OXPHOS:

Oxidative phosphorylation

PDH:

Pyruvate dehydrogenase

PDK:

Pyruvate dehydrogenase kinase

PFK:

6-Phosphofructo-1-kinase

PFKFB:

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase

PK:

Pyruvate kinase

PKM2:

Pyruvate kinase isoform M2

PP pathway:

Pentose phosphate pathway

PYR:

Pyruvate

RLM:

Rat liver mitochondria

ROS:

Reactive oxygen species

VDAC:

Voltage-dependent anion channel

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  1. Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari (IBIOM)-CNR, Via G. Amendola 165/A, 70126, Bari, Italy

    Lidia de Bari & Anna Atlante

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  1. Lidia de Bari
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  2. Anna Atlante
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Correspondence to Lidia de Bari.

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de Bari, L., Atlante, A. Including the mitochondrial metabolism of l-lactate in cancer metabolic reprogramming. Cell. Mol. Life Sci. 75, 2763–2776 (2018). https://doi.org/10.1007/s00018-018-2831-y

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