Are mitochondrial dysfunctions associated with cancer?

Human cells contain mitochondria, a semi-autonomous cell organelle that is the cell’s primary energy source. These tiny organelles are protected by double sacs and are mainly responsible for producing adenosine triphosphates (ATPs), the cell’s energy currency. ATPs are critical in powering different pathways and metabolism inside the cell. ATPs are also crucial in powering muscles and allowing muscle cells to contract and perform their function. 

In recent years, mitochondria have been implicated in the metabolism of cancer cells. However, it is first necessary to examine what are tumour cells and cancer cells and why mitochondria are involved in cancer metabolism. 

What are tumours and cancer cells? 

Tumours are described as abnormal tissue masses that develop when cellular growth and division become uncontrolled [1]. Cells exposed to continuous oxidative stress and toxic compounds and chemicals may undergo cellular dysfunction leading to unchecked growth and division. Most of these cells sustain DNA damages that would lead to indefinite and continuous divisions and multiplications. Daughter cells produced from these cells have different phenotypes and altered cellular mechanisms. 

Tumours are groups of cells with altered cellular mechanisms and are categorised as benign or malignant tumours [1]. Benign tumours contain cells that do not invade lymph nodes and surrounding blood vessels, while malignant tumours are cancer cells that have invaded lymph nodes and blood vessels and spread to other parts of the body. Malignant tumours are also called neoplasms. 

What are the features and functions of the mitochondria? 

The mitochondria are regarded as semi-autonomous organelle bounded by a double membrane. It has an inner membrane called cristae and an outer membrane. A single cell can contain thousands of mitochondria, with these organelles occupying 25% of the cell’s cytoplasm [2]. 

The mitochondria are responsible for lipid, glutamine and glucose metabolism. The primary function of the mitochondria is to ensure that Krebs cycle and aerobic respiration are successfully carried out, and ATPs are generated in the end. The energy derived from ATP is critical in the survival of the cells. 

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What is the role of mitochondria in cancer development? 

A distinct characteristic of the mitochondria involves the presence of its DNA. This unique feature of the mitochondria is that it possesses circular and supercoiled genetic materials called mitochondrial DNA (mtDNA). The mtDNA encodes tRNAs, rRNAs and proteins necessary for oxidative phosphorylation, electron transport and generic repair. The mtDNA encodes a total of 13 proteins. Mitochondrial DNA mutations have been found in several human cancers. These mutations can be found in the rRNA and tRNA genes and the protein-coding regions. 

Discovered in 1963, the mitochondrial DNA codes 37 genes, with some of these genes interacting with genes in the cell’s nucleus. Researchers found out that in cancer cells, mutations of the genes in the mitochondria can alter the behaviour of nuclear and mitochondrial protein complexes. Changes in biochemical behaviour lead to increased reactive oxygen species (ROS) production. 

ROS are byproducts of oxygen metabolism and alter cellular functions when present in increased amounts. It is believed that high levels of ROS can enable tumour growth. Hence, mutations in the genes of the mitochondria can directly affect tumour growth and development. These studies show that the mitochondria can influence the functions of both malignant and normal cells [2]. 

Research evidence [3] also showed that depletion of the mitochondria and a wide range of mtDNA deletions are a precursor of cancer initiation and spread. Currently, urologists who treat prostate cancer use this information to determine if mitochondrial genome deletion could identify the presence or absence of cancer. A 3.4kb mitochondrial genome deletion is used to detect the presence or absence of prostate cancer who have an initial biopsy that is benign [4]. 

What are the characteristics of cancer cells? 

Cancer cells demonstrate altered metabolism and redox status. It should be noted that the mitochondria are the central organelle where ROS and ATP are produced. Mitochondrial dysfunction induced by the following has been implicated in cancer formation: 

  • Alterations in the genome of the mitochondria 
  • Modifications in the Kreb’s cycle enzymes
  • Alterations in the mitochondrial electron transport chain 
  • Oxidative stress due to excess generation of ROS

Within the mitochondria, proteins have been identified that suppress tumour signalling and suppress expressions of dysfunctional genes. However, when these proteins also become dysfunctional, this could lead to the proliferation of tumours and cancer cells. 

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Current study on mitochondrial biomarker of cancer 

In a study led by Kossenkov and his colleagues [5], findings revealed that a gene associated with mitochondrial dysfunction is also linked to aggressive cancer subtypes. This molecular signature is associated with low patient survival rates as patients become treatment resistant. This mitochondrial protein, called Mic60, has been implicated in poor patient outcomes in those with cancer. 

What is Mic60? 

Mic60 is known as IMMT or inner membrane mitochondrial protein. It is also called mitfilin, an essential protein required for building the structure of the mitochondria. Mic60 or mitofilin has an impact on tumour metabolism and mitochondrial functions. 

What are the actions of Mic60? 

Kossenkov collaborated with several researchers from other countries [5] and discovered that an 11-gene Mic60-low signature is associated with treatment failure, aggressive disease or cancer, shortened survival and local inflammation. 

Findings reported that the Mic60-low gene signature could be used to examine the disease’s stage and predict patients’ response to treatment. As shown in the study, the 11-gene Mic60-low signature could be used as a biomarker or simple tool to estimate the risk for specific cancers such as pancreatic ductal adenocarcinoma and, potentially, other forms of cancer. 

However, the Mic60 as a biomarker must be verified in more extensive clinical trials. Results from these future trials will help inform clinicians and investigators if the 11-gene Mic60-low signature is a valuable tool in predicting or estimating cancer risk and determining which group of patients would most likely respond to treatment. 

Are there still gaps in understanding how mtDNA mutations lead to cancer? 

Mitochondrial mutations appear to be expected, as many cancers present with mtDNA mutations. However, the causal roles of mtDNA mutations in cancer development are still not completely understood. There are still many concerns and issues on how mtDNA mutations cause cancer that remain unanswered. An understanding of why specific mtDNA mutations are more prevalent in one type of cancer and not in a different kind of cancer is needed to understand the formation of cancer better. This difference may be partly due to the mechanisms of different types of cancers. Notably, other cancer types’ mechanisms of cancer development are not universal. There are differences in cancer pathways, which could explain differences in the number of mitochondrial mutations. 

Mitochondrial DNA mutations could occur in the electron transport or respiratory chain, leading to oxidative stress. It should be noted that mild to moderate mitochondrial dysfunction could lead to the generation of ROS, while severe dysfunction of the mitochondria can lead to cellular death. In turn, this leads to tumour growth inhibition as cells undergo death or apoptosis. 

Understanding the mitochondria’s complex involvement in cancer development would help healthcare practitioners design better treatments for their patients. More excellent knowledge on how cancers are formed could inform investigators and clinicians which proteins and mechanisms to target to prevent cancer. Finally, identifying the biomarkers of mitochondrial dysfunctions may be vital in predicting patient outcomes and treatment of specific cancers. 

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