Recent literature shows that cancer cells have a different electron transport chain mechanism from normal cells and both of cancer cells and normal cells use NADH as electron donors. So, is there a difference in the number of electron donors required between cancer cells and normal cells? What possible mechanisms could explain this difference?

enter image description here


Huang, Huaiyi, Samya Banerjee, Kangqiang Qiu, Pingyu Zhang, Olivier Blacque, Thomas Malcomson, Martin J. Paterson et al. "Targeted photoredox catalysis in cancer cells." Nature Chemistry 11, no. 11 (2019): 1041-1048.

Kim, S. Y. (2018). Cancer energy metabolism: shutting power off cancer factory. Biomolecules & Therapeutics, 26(1), 39.

  • 1
    $\begingroup$ Could you please explain in your own words what is proposed. It is not apparent from the figure and “different ETC mechanism” conjures up some alternative form of the various complexes, which is highly improbable. I am not going to read the original paper to find out — questions here should be comprehensible in themselves. $\endgroup$
    – David
    Sep 16, 2022 at 17:11
  • $\begingroup$ Also see Warburg effect. en.wikipedia.org/wiki/Warburg_effect_(oncology) $\endgroup$ Sep 16, 2022 at 23:46
  • $\begingroup$ "MAS" (according to one of the papers you quote) is the malate-aspartate shuttle. That is, electrons from cytosolic NADH cross the mitochondrial membrane, but the inner mitochondrial membrane is impermeable to NAD(H), a key point not very clear from your diagram/description $\endgroup$
    – user338907
    Sep 17, 2022 at 11:36

1 Answer 1


Short answer:

Yes, NADPH is definitely enriched in cancer cells, since cancer tends to rely more on glycolysis. That way, much less NADH is consumed into the electron chain. It was even proposed to treat cancer using NAD+ precursors to shift NAD/NADH balance: Santidrian et al. 2013

Tumor cells also generate high levels of reduced forms of NAD+, NADH, and NADPH as important cofactors and redox components (4, 5). These altered metabolic activities can be linked to mitochondrial dysfunction that inhibits OXPHOS, increases ROS, promotes uncontrolled growth, and causes DNA damage that further supports a metastatic phenotype

The energy metabolism in cancer might be one of the most skewed and dysregulated aspect of any cancer cell.

One reason is actively discussed: Hypoxia. Cancer grows. Fast. Faster than blood vessels can grow into the tumor to support it with oxygen. So the tumor is constantly suffocating. That's why cancer relies on oxygen independent metabolism (Glycolysis, aka the "Warburg effect"). In the later stages of cancer transformation however, it seems that a cancer cell can re-activate oxidative phosphorylation (OXPHOS, or mitochondrial electron chain with oxygen as terminal electron acceptor).

This review (Zheng 2012) name some very interesting reasons why that is the case:

Glycolysis yields more metabolic precursors for growth

i) Glycolysis is more suitable for cancer growth. Since proliferation of cancer tissues is faster than normal tissues, it not only needs energy, but also needs metabolic intermediates for the biosynthesis of macromolecules. Many intermediates from glycolysis and the truncated TCA cycle can be used to synthesize macromolecules, such as nucleic acids, lipids and proteins, which are required for cancer growth and proliferation (2,30).

Glycolysis generates Energy Quicker (despite being inefficient)

ii) Too efficient products of ATP may not a good thing for cancer cells. If cancer cells use high-efficiency glucose, ADP is converted to ATP. The high concentration of ATP will inhibit phosphofructokinase 1 (PFK1), the rate-limiting enzyme in glycolysis and pyruvate kinase 1 (PK1), and glycolysis will be inhibited. Inhibited glycolysis is unfavorable for cancer cell growth. Although glycolysis yields less ATP than OXPHOS, the speed of ATP generation in the former is quicker than in the latter, which is suited to the energy demands of rapid proliferation tissues such as cancer and embryonic tissues (11). Generally speaking, rapid proliferation tissues rely more on glycolysis for ATP production whereas differentiation tissues rely primarily on OXPHOS for energy production (13,31). If using glycolysis inhibitor 3-bromopyruvate (3-BP) treats tumors, it is more efficient for rapid growth of tumors than slow growth of tumors.

Glycolysis enhances Invasion

iii) Hypoxia is often observed in cancer tissues, and glycolysis offers growth advantage of cancers under this hypoxic environment (4). Glycolysis produces lactate which is released into the extracellular space. An acidic microenvironment provides a growth advantage to cancer tissues over normal tissues and enhances the invasion and metastasis of cancer cells (32,33). In addition, lactic acidosis inhibits glycolysis and favors aerobic respiration as a means of energy generation (14).

Glycolysis is less Cytotoxic

iv) Due to the decrease of mitochondrial OXPHOS, less reactive oxygen species (ROS) are generated, which are cytotoxic to cancer cells (34,35).


You must log in to answer this question.

Not the answer you're looking for? Browse other questions tagged .