Abstract
The combined derangements in mitochondria network, function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways. In hematological malignancies, there is a strong relationship between cellular metabolism, mitochondrial bioenergetics, interconnections with supportive microenvironment and drug resistance. Lymphoma and chronic lymphocytic leukemia cells, e.g., adapt to intrinsic oxidative stress by increasing mitochondrial biogenesis. In other hematological disorders such as myeloma, on the contrary, bioenergetics changes, associated to increased mitochondrial fitness, derive from the adaptive response to drug-induced stress. In the bone marrow niche, a reverse Warburg effect has been recently described, consisting in metabolic changes occurring in stromal cells in the attempt to metabolically support adjacent cancer cells. Moreover, a physiological dynamic, based on mitochondria transfer, between tumor cells and their supporting stromal microenvironment has been described to sustain oxidative stress associated to proteostasis maintenance in multiple myeloma and leukemia. Increased mitochondrial biogenesis of tumor cells associated to acquisition of new mitochondria transferred by mesenchymal stromal cells results in augmented ATP production through increased oxidative phosphorylation (OX-PHOS), higher drug resistance, and resurgence after treatment. Accordingly, targeting mitochondrial biogenesis, electron transfer, mitochondrial DNA replication, or mitochondrial fatty acid transport increases therapy efficacy. In this review, we summarize selected examples of the mitochondrial derangements in hematological malignancies, which provide metabolic adaptation and apoptosis resistance, also supported by the crosstalk with tumor microenvironment. This field promises a rational design to improve target-therapy including the metabolic phenotype.
Highlights
Since the first description by Rudolf Albrecht von Kölliker in 1857, scientists have explored the essential roles of mitochondria in cell biology, as the powerhouse of the cells able to produce comparing weight to weight, thousands of times more energy per second as compared to sun production [1]
Mitochondria can fuel cellular energy demands by using as substrate pyruvate, arising from glycolysis or lipolysis coupled to b-oxidation of fatty acids (FA), in the oxidative-phosphorylation (OX-PHOS) process coupled to the electron transport chain (ETC)
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression is significantly correlated with the percentage of ATP generated from glycolysis, so low GAPDH level is related to oxygen consumption in OX-PHOS -diffuse large B cell lymphoma (DLBCL) while high GAPDH level is related to lactate production in B cell receptor (BCR)-DLBCLs
Summary
Since the first description by Rudolf Albrecht von Kölliker in 1857, scientists have explored the essential roles of mitochondria in cell biology, as the powerhouse of the cells able to produce comparing weight to weight, thousands of times more energy per second as compared to sun production [1]. Mitochondria can fuel cellular energy demands by using as substrate pyruvate, arising from glycolysis or lipolysis coupled to b-oxidation of fatty acids (FA), in the oxidative-phosphorylation (OX-PHOS) process coupled to the electron transport chain (ETC). The combined derangements in mitochondria network function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways [2]. There is a gap in knowledge about the protein composition, structure and dynamics of lipid droplet– mitochondria structures and how bidirectional FAs exchange occur, even if the strong relationship between cellular metabolism, mitochondrial bioenergetics, and tumorigenesis development is an established emerging hallmark [2, 3]. We will summarize the most advanced body of knowledge about the mitochondrial derangements in hematological malignancies which provide metabolic adaptation and apoptosis resistance, with a particular focus on the implication of novel relevant targets to reduce the risk of recurrence (Figure 1)
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