Mitochondria – secret keepers of the haematological functions?

Mitochondria are tiny organelles found in eukaryotic cells. They are widely known as the “powerhouse of the cell”. Mitochondria’s key role is energy production in terms of ATP synthesis, which involves a process called oxidative phosphorylation. Furthermore, mitochondria are involved in many different processes like cell death regulation, hormone synthesis, cell-stress control and calcium levels. Mitochondria are also the primary source of endogenic reactive oxygen species (ROS). Disrupting the equilibrium of all named processes leads to cell death, lowered energy production capacity, and immunological function disorder, consequently leading to mitochondrial dysfunction. Mitochondrial dysfunction harms many organ systems, including the haematological system.

Mitochondrial function

Mitochondria are, in many ways, involved in the homeostasis of haematopoetic cells. The key processes required for understanding mitochondrial function are oxidative phosphorylation and apoptosis. Oxidative phosphorylation is a process in which electrons are first produced and then transferred by oxido-reduction reactions across many electron carriers until they are finally delivered to the oxygen molecule. Protons are pumped through the inner mitochondrial membrane into the intermembrane space, consequently creating an electrochemical gradient. Mitochondrial ATP synthase will, in the end, produce ATP; in other words, energy is being made in this process. Furthermore, mitochondria contain many proapoptotic signals. Protoapoptotic Ccl-2 proteins in the mitochondrial membrane encourage the production of specific PT pores (Permeability Transition pores) through which many molecules acting as proapoptotic signals, including cytochrome C, can exit the mitochondria. These processes lead to a cascade reaction involving caspases, resulting in DNA fragmentation, condensation and cell phagocytosis.

Mitochondrial dysfunction and anaemias

Anaemia is a pathological condition characterised by lowered red blood cells or haemoglobin levels. There are many causes of this condition, including mitochondrial dysfunction. Mitochondria are the key to energy production needed for haemoglobin synthesis. Haemoglobin, found in erythrocytes, is the primary protein for oxygen transfer. Moreover, mitochondrial dysfunction lowers the cell capacity for haemoglobin production and hence lowers the number of mature erythrocytes, leading to anaemia development.

One of the most prominent examples of mitochondrial dysfunction causing sideroblastic anaemia is Pearson’s syndrome, a rare genetic disorder caused by significant deletions in the mitochondrial genome. Pearson’s syndrome occurs in infancy and is characterised by haematopoetic cell dysfunction involving lowered blood cell levels of all three groups (erythrocytes, leukocytes and thrombocytes). In the bone marrow of these patients, there are pathological erythrocyte precursors called ring-shaped sideroblasts. Ring sideroblasts are familiar to all sideroblastic anaemias and contain excessive iron deposits. Steps in heme synthesis, iron metabolism and Fe-sulphuric clusters (Fe-S) biogenesis that involve mitochondria are essential in erythrocytes. Defects in some of the said steps result in iron accumulation, leading to the development of ring sideroblasts and immature erythrocytes and hence, anaemia develops.

Mitochondrial dysfunction and leukaemias

Leukaemia stands for malignant blood cancer that can be linked to mitochondrial dysfunction. In healthy cells, mitochondria start apoptosis when the cell is damaged or abnormal. However, in malignant conditions like leukaemia, mitochondrial dysfunction prevents timely apoptosis and allows the proliferation and survival of abnormal blood cells. Moreover, reactive oxygen species produced by mitochondria can cause DNA damage and genetic mutations that increase the risk of leukaemia. For example, acute myeloid leukaemia (AML) is a devastating malignant disease characterised by the uncontrolled spread of nondifferentiated myeloid progenitor cells called blasts.  Mutations in the mitochondrial enzyme isocitrate dehydrogenase-2, which is the oncogenic promotor of AML, are observed. Mutation results in lowered ATP synthase activity and mitochondrial energy metabolism.

A particularly high percentage of changed structures of mitochondrial DNA is noticed in leukaemia cells. After chemotherapy, the percentage of changed structures decreases, showing that a dynamic increase of mitochondrial mutations characterises the progress of haematological malignancy. Mitochondrial DNA mutations are also present in cytochrome C, one of the crucial pro-apoptotic signalling molecules. Moreover, one of the possible causes for the creation of incorrect nucleotides is genotoxic stress. Genotoxicity is a chemical property and a property of other environmental factors that cause genetic material damage inside the cell. Genotoxic stress leads to oxidation catalysed by ROS, creating incorrect nucleotides in the DNA, which leads to the loss of cell integrity; that is, it causes cell death (apoptosis) or malignant cell transformations.

Mitochondrial dysfunction and thrombocytopathy

Mitochondria play an essential role in keeping the thrombocyte levels in control. Hence, their dysfunction can cause thrombocytopathies and disorders of thrombocyte function, leading to an increased likelihood of haemorrhage or thrombosis. Mitochondria are the powerhouse of the cell; as such, they produce the energy needed for thrombocyte activation and the beginning of the coagulation reaction. Let us remind ourselves that the mitochondria are essential organelles involved in managing internal calcium levels. Calcium is the key element of thrombocyte activation, and mitochondria are the ones involved in releasing calcium inside the thrombocyte. Furthermore, ROS that mitochondria have created are also involved in activating thrombocyte activation pathways. In conditions of mitochondrial dysfunction, too many reactive oxygen species are created, leading to blood coagulation disturbances. One such example is the deficiency of the MTH1 (human mutT Homolouge 1) enzyme. MTH1 is crucial in protecting the mitochondrial DNA from oxidative stress, and its deficit can lead to all of the stated problems linked to the thrombocyte function, including the damage of mitochondrial DNA, decreased energy production, disrupted haemostasis and thrombosis.

Mitochondria – new therapeutic target?

From all of the above, it is clear that the mitochondria play a crucial role in the functionality of haematopoetic cells and that their dysfunction can cause severe haematological disorders. Recent advancements in understanding mitochondrial function and metabolism provide possibilities for developing new therapeutics to help cure haematological diseases by targeting mitochondria. Moreover, past and future research could help discover new biomarkers for diagnosis and monitoring of patients with said conditions, which will, for sure, enable more precise and personalised treatment.

                                                                                                          Translated by: Dea Radek