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Cancer’s Thieving Ways

Mitochondria are essential for tumour growth, not for energy production but to enable cancer cells to synthesise nuclear DNA. Wire_man/Adobe

Mitochondria are essential for tumour growth, not for energy production but to enable cancer cells to synthesise nuclear DNA. Wire_man/Adobe

By Jiri Neuzil, Lanfeng Dong & Mike Berridge

Shutting down the mechanisms that enable developing tumours to steal mitochondria from the cells around them opens the way to a broad-spectrum treatment for a vast array of cancers.

Mitochondria are energy-generating organelles in most of the cells within complex organisms. They originated when specialised bacteria were engulfed by other primitive cells two billion years ago.

Today, mammalian mitochondria retain a minute circular genome that’s about 180,000 times smaller than our nuclear genome. While it was long-ignored by geneticists, the role of mitochondrial DNA in human disease is now well-established. Furthermore, many nuclear genes that are essential for mitochondrial respiration have been identified.

While our nuclear genome has about 22,000 genes inherited from both parents, mitochondria are maternally inherited and have only 37 genes. Thirteen of these mitochondrial genes encode proteins that are essential for respiration, while the remaining 24 make RNA molecules for the specialised protein machinery that forms these 13 respiratory proteins.

In 2015 our research showed that tumour cells that lack mitochondrial DNA will not develop into tumours unless they can acquire mitochondria from surrounding cells. While normal cancer cells will form tumours in mice within 7–10 days, cancer cells without mitochondrial DNA take 20–30 days to start forming tumours, during which time they acquire mitochondria from nearby non-cancer cells.

How mitochondria move between cells in animals is not known, but membrane bridges and cell-to-cell transfer by extracellular vesicles have been demonstrated in cell culture systems. We have observed the formation of intercellular bridges (often referred to as tunnelling nanotubes), with mitochondria moving along tubulin fibres in these bridges from donor cells to cancer cells that lack mitochondrial DNA. We do not know what signals are used by cancer cells under mitochondrial stress to entice donor cells to provide mitochondria for respiration recovery, but are using cutting-edge methodologies to solve this problem.

Tumour cell lines that lack mitochondrial DNA are respiration-deficient and unable to use their mitochondria to generate ATP. However, they can be maintained in the laboratory without mitochondrial DNA if they are provided with uridine, which is a precursor of the DNA nucleotides cytosine and thymine. Without uridine they can only form tumours if they can acquire mitochondria from surrounding cells.

In contrast, parental tumour cells whose mitochondrial respiration is intact yet lack a nuclear gene necessary for mitochondrial ATP synthesis can form tumours. Thus, mitochondrial energy is not required for tumour growth. Instead, tumour cells that cannot use their mitochondria to make ATP produce energy by glycolysis.

This would appear to be inefficient, producing only two ATP molecules per glucose consumed compared with 34 ATPs when mitochondria are fully functional. Nevertheless, tumour growth can occur if mitochondrial respiration is intact, as mitochondrial electron transport and respiration are also required to produce cytosine and thymine.

A key mitochondrial enzyme that is needed to make cytosine and thymine, dihydro-orotate dehydrogenase (DHODH), depends on mitochondrial electron transport and respiration for its activity. When the nuclear gene for this enzyme is knocked out, tumour formation fails. However, coupling respiration with mitochondrial ATP production is not essential for tumour growth.

These results indicate that inhibiting the enzyme necessary for DNA synthesis and cell proliferation, but not mitochondrial energy production, could halt tumour growth. We have shown this in our recent Cell Metabolism paper (https://goo.gl/JRYxAA) for tumour types a different as breast cancer and melanoma.

It is reasonable to expect that respiration-coupled synthesis of the DNA nucleotides cytosine and thymine will be inherent to most types of tumours. Therefore, targeting DHODH and mitochondrial respiration may be a novel, broad-spectrum and efficient approach to treating a range of tumours.

Novel agents are currently being prepared that target DHODH and respiration in general. One agent that has been synthesised recently targets mitochondrial respiration by inhibiting the function of the respiratory complex I, and is currently in clinical trial.

Mitochondria are intriguing targets for cancer therapy, but have been vastly underutilised. There has been some skepticism about developing efficient anti-cancer agents due to the unprecedented capability of cancer cells to adjust to various environmental stresses and acquire resistance when challenged with established anti-cancer drugs. Since drugs targeting a single pathway or a product of a single gene are unlikely to suppress tumours efficiently, what is needed is an invariant target in cancer cells that is essential for tumour progression across the wide landscape of neoplastic diseases. Mitochondria appear to present such a target.

Agents such as mitochondrially targeted tamoxifen and novel drugs targeting DHODH may be particularly efficient in tumour suppression as part of combination therapies. Combining these treatments with cancer immunotherapy approaches is expected to provide additional benefits.


Jiri Neuzil is Head of the Mitochondria, Apoptosis and Cancer Research Group at Griffith University’s School of Medical Science, where Lanfeng Dong is a Senior Research Fellow. Mike Berridge is a Distinguished Research Fellow and Senior Scientist at the Malaghan Institute of Medical Research.