SATURDAY, 30 DECEMBER 2023
Preface
I’m a PhD student in the Dept of Medicine at the University of Cambridge studying the role of mitochondrial biology in governing immunometabolic underpinnings of cytotoxic T lymphocyte exhaustion and senescence in the context of cancer and aging. One of the best things about my PhD has been to explore an area of science so incredibly new, novel and complex and I’d love to take this opportunity to educate the general public on this very intriguing area of immunology and metabolism research, that sure holds the key to ground-breaking therapeutic advances in the near future.
Introduction:
Mitochondria, often dubbed as the cellular powerhouses, have undergone a transformative re-evaluation in recent decades. Initially perceived solely as energy producers through oxidative phosphorylation, these dynamic organelles are now recognized as integral components orchestrating a symphony of immunometabolic processes vital for cellular homeostasis. The historical perspective reveals a paradigm shift from viewing mitochondria as passive contributors to energy production to active participants in cellular societies, influencing a myriad of physiological functions. Initially discovered in the late 19th century, mitochondria were predominantly regarded as static entities with a singular function: ATP production. However, with advancements in microscopy and molecular biology, researchers began uncovering the dynamic nature of these organelles. This evolving understanding forms the basis for exploring the multifaceted roles of mitochondria in cellular function, extending beyond energy metabolism to encompass immunometabolic regulation.
Mitochondrial Networking:
Mitochondrial Fusion and Fission:
Mitochondrial dynamics, governed by fusion and fission processes, play a pivotal role in shaping the morphology and, therefore, function of these organelles. Mitochondrial fusion involves the merging of individual mitochondria, promoting the exchange of genetic and functional components. Contrastingly, fission is the process of mitochondrial division, facilitating the segregation of damaged components. The delicate balance between fusion and fission is crucial for maintaining a healthy mitochondrial network and responding to cellular energy demands.
Molecular players, including dynamin-related GTPases, orchestrate these processes. Proteins such as Mfn1/2 and Opa1 mediate fusion, ensuring the interconnection of mitochondria, while Drp1 governs fission, allowing for the removal of dysfunctional mitochondrial segments. Dysregulation in these processes can lead to mitochondrial fragmentation or elongation, influencing cellular bioenergetics, apoptosis, and reactive oxygen species (ROS) production.
Intercellular Mitochondrial Transfer:
Recent discoveries have unveiled the phenomenon of intercellular mitochondrial transfer, challenging the conventional notion of mitochondria as strictly intracellular entities. Cells can exchange mitochondria, promoting cellular repair and enhancing resilience to stress. This intercellular mitochondrial trafficking is particularly relevant in scenarios where damaged cells can be rescued by the incorporation of healthy mitochondria from neighboring cells. The implications of this phenomenon extend to tissue homeostasis, regeneration, and the establishment of a functional mitochondrial network within multicellular organisms.
Immunometabolic Crosstalk:
Mitochondria and Inflammation:
Mitochondria serve as key regulators of inflammation, participating in both the initiation and resolution of immune responses. The release of mitochondrial components, such as mitochondrial DNA (mtDNA) and mitochondrial-derived peptides, can activate innate immune pathways, leading to inflammation. On the other hand, mitochondria also play an essential role in the resolution of inflammation by influencing macrophage polarization and promoting anti-inflammatory responses. Dysfunctional mitochondria, often observed in various pathological conditions such as autoimmune diseases and cancer, contribute to chronic inflammation and immune dysregulation.
Metabolic Reprogramming:
Mitochondria actively participate in metabolic reprogramming, adapting cellular metabolism to meet the specific demands of immune cells. During immune activation, there is a shift towards glycolysis from oxidative phosphorylation, known as the Warburg effect, providing rapid energy for effector functions. Mitochondria contribute to this metabolic switch by regulating the tricarboxylic acid (TCA) cycle and influencing the balance between glycolysis and oxidative phosphorylation. Understanding these metabolic adaptations is crucial for deciphering immune cell function in health and disease.
Mitochondria and Cancer Immunometabolism:
Warburg Effect and Tumor Immune Microenvironment:
The Warburg effect in cancer cells not only shapes the metabolic landscape but also profoundly influences the tumor immune microenvironment. The high glycolytic activity of cancer cells results in the accumulation of lactate and acidic conditions, creating an immunosuppressive milieu. Mitochondrial dynamics play a crucial role in modulating the metabolic interactions between cancer cells and immune cells within the tumor microenvironment.
Mitochondria in cancer immunometabolism exhibit dynamic changes, impacting the functions of immune cells. Tumor-infiltrating lymphocytes, for example, undergo metabolic reprogramming influenced by mitochondrial dynamics. Alterations in mitochondrial fusion and fission events within immune cells can impact their effector functions, cytokine production, and overall anti-tumor responses. Understanding these intricate interactions provides insights into the design of immunotherapies that leverage the metabolic vulnerabilities of both cancer cells and immune effectors.
Mitochondria and Immune Evasion:
Mitochondria are implicated in the complex interplay between cancer cells and the immune system, influencing immune evasion mechanisms. Dysfunctional mitochondria in cancer cells can release mtDNA and other damage-associated molecular patterns (DAMPs) that activate immune responses. However, certain cancers exploit these mitochondrial signals to induce immunosuppression, creating an environment conducive to tumor growth. Mitochondrial dynamics in cancer cells may contribute to the evasion of immune surveillance. Mitochondrial fusion can shield cancer cells from immune recognition by promoting the exchange of mitochondrial components and reducing the release of immunogenic signals. Targeting these mitochondrial mechanisms holds potential for developing novel immunotherapies aimed at enhancing anti-tumor immune responses and overcoming immune evasion in cancer.
Mitochondria and Aging Immunometabolism:
Mitochondrial Dysfunction in Age-Related Immunosenescence:
Aging is accompanied by changes in the immune system, a process known as immunosenescence, characterized by decreased immune function and increased susceptibility to infections and chronic diseases. Mitochondrial dysfunction is a central contributor to age-related immunosenescence. The decline in mitochondrial function compromises the bioenergetic capacity of immune cells, impacting their responsiveness and functionality.
Mitochondrial dynamics also play a role in age-related changes in immune cells. Altered mitochondrial fusion and fission events contribute to the accumulation of dysfunctional mitochondria in aged immune cells, impairing their ability to mount effective immune responses. These changes are particularly relevant in the context of chronic low-grade inflammation, termed inflammaging, which is associated with various age-related diseases.
Immunometabolic Interventions for Age-Related Immune Decline:
Understanding the immunometabolic aspects of aging opens avenues for interventions aimed at preserving immune function in older individuals. Strategies that target mitochondrial health, such as mitochondrial antioxidants and modulators of mitochondrial dynamics, have the potential to mitigate age-related immunosenescence. Caloric restriction and exercise, known to influence both mitochondrial function and immune responses, emerge as promising lifestyle interventions for promoting healthy aging and preserving immune resilience.
Mitochondrial Epigenetics in Immunology:
Mitochondrial DNA Methylation and Immune Cell Function:
Recent advances in the field of mitochondrial epigenetics highlight the role of mtDNA methylation in modulating immune cell function. Changes in mtDNA methylation patterns have been associated with alterations in immune cell activation, cytokine production, and overall immune responses. The crosstalk between nuclear and mitochondrial epigenetics is particularly intriguing in the context of immunology, as epigenetic modifications within mitochondria may influence the expression of immune-related genes.
Histone modifications within mitochondria also contribute to the regulation of immune cell function. The acetylation and methylation of mitochondrial histones play a role in modulating mitochondrial gene expression and oxidative phosphorylation. Unravelling the epigenetic landscape within mitochondria provides a novel perspective on the regulation of immune responses and may offer new therapeutic targets for immune-related disorders.
Environmental Influences on Mitochondrial Immunometabolism:
Impact of Environmental Toxins on Immune Cells:
Environmental toxins can profoundly influence the immunometabolism of immune cells through their effects on mitochondrial function. Exposure to pollutants and toxins can lead to mitochondrial dysfunction in immune cells, impairing their ability to mount effective immune responses. Mitochondria act as sensors of environmental stress, and their dysfunction contributes to immune dysregulation observed in individuals exposed to environmental toxins.
Mitochondria and Immune Adaptation to Hypoxia:
Mitochondria play a crucial role in immune cell adaptation to hypoxic conditions, a common feature of inflamed and tumor microenvironments. Immune cells, when exposed to low oxygen levels, undergo metabolic reprogramming facilitated by changes in mitochondrial function. Understanding how mitochondria mediate immune cell adaptation to hypoxia (low oxygen conditions) is crucial for deciphering immune responses in conditions such as chronic inflammation and cancer.
Mitochondria in Stem Cell Immunometabolism:
Mitochondria in Pluripotency, Differentiation, and Immune Modulation:
Mitochondria are pivotal in regulating the immunometabolism of stem cells, influencing their pluripotency, differentiation, and immunomodulatory functions. Pluripotent stem cells exhibit unique mitochondrial features that support their immunomodulatory potential. As stem cells differentiate into immune cells, mitochondrial dynamics play a role in shaping the metabolic and functional properties of these cells.
Stem cell-based immunotherapies, harnessing the immunomodulatory potential of stem cells, are being explored for treating various immune-related disorders. Understanding the role of mitochondria in stem cell immunometabolism provides insights into optimizing these therapeutic approaches and tailoring them for enhanced immune modulation.
Conclusion:
In conclusion, mitochondria are central players in the immunometabolism of various physiological and pathological processes, including cancer and aging. The interplay between mitochondrial dynamics, immunometabolism, and immune cell function shapes the outcomes of immune responses in health and disease. A deeper understanding of these interactions opens avenues for developing targeted immunotherapies that leverage the metabolic vulnerabilities of cancer cells, mitigate age-related immunosenescence, and modulate immune responses in various disorders. Integrating the immunological perspective into mitochondrial biology enriches our understanding of cellular function and provides novel therapeutic opportunities for diseases with immune involvement.
Article by Swetha Kannan
Image credit: Science Photo Library
Image licence: CC BY-NC 4.0 DEED Attribution-NonCommercial 4.0 International
The original image has been cropped.
