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Leaking 'cell batteries' called mitochondria cause many human diseases

Scientists have uncovered the mechanism by which “leaky” mitochondria, the cell’s energy factories, can trigger harmful inflammation and disease.

This research has shed light on a fundamental biological process with far-reaching implications for treating chronic inflammatory diseases, such as lupus and rheumatoid arthritis.

It could pave the way for developing more effective therapies for these conditions, enhancing our immune response to viral infections, and potentially slowing the aging process.

Cell powerhouses under siege

Mitochondria possess their unique genetic material, distinct from the cell’s nuclear DNA. It has been known that mitochondrial DNA (mtDNA) can escape into the cell, sparking inflammation. However, the exact trigger for this escape has eluded scientists until now.

The recent findings illustrate how mtDNA leakage prompts the body to initiate a damaging immune response, which can lead to autoimmune and chronic diseases.

Laura E. Newman, PhD, from the University of Virginia School of Medicine, explains the significance of this discovery.

“When mitochondria fail to properly manage their DNA, attempts to dispose of the excess can lead to inflammation. Understanding this process opens the door to interventions that could mitigate inflammation and its consequences,” Newman said.

From mitochondrial leaks to inflammation and disease

Gerald Shadel, PhD, and his team, including Newman, utilized advanced imaging and cell biology techniques to trace the mtDNA’s journey out of the mitochondria.

They discovered that malfunctions in mtDNA replication cause protein accumulations, leading to the cell’s attempt to eliminate these excess nucleoids. However, the cellular waste disposal system, or endosomes, can get overwhelmed, resulting in mtDNA spilling into the cell.

“We observed mtDNA within a mysterious membrane structure post-leakage, leading us to identify the endosome’s role in this process. This breakthrough points to a novel mechanism of mtDNA disposal and leakage,” said Newman.

The cell identifies the leaked mtDNA as foreign, triggering an immune response akin to fighting off a virus, but this also results in detrimental inflammation.

Implications for health and disease

Uri Manor, PhD, emphasized the novelty of their discovery and its potential to answer critical questions about the interaction between cellular components, the variance in mtDNA release among different cell types, and strategies to reduce inflammation associated with diseases and aging.

In her new position at the UVA School of Medicine’s Department of Cell Biology, Newman aims to delve deeper into the conditions under which this mitochondrial pathway is activated.

This includes exploring how viruses targeting mitochondria could exploit this pathway to alarm against infections and whether its overactivation could lead to chronic diseases.

Targeting mitochondria to fight disease

In summary, this important discovery of how “leaky” mitochondria contribute to harmful inflammation opens new doors for treating autoimmune and chronic diseases, fighting viral infections, and potentially slowing the aging process.

The UVA School of Medicine team has elucidated the pathway through which mitochondrial DNA escapes and incites an immune response, while laying the groundwork for future therapies aimed at mitigating this inflammation.

This pivotal research underscores the intricate link between cellular processes and human health, promising a future where targeted interventions can effectively combat inflammation-related diseases, enhancing our overall well-being and longevity.

More about mitochondria and disease

As discussed above, mitochondria, often hailed as the powerhouses of our cells, play a pivotal role in generating the energy necessary for cellular functions.

Embedded within the cytoplasm of nearly every cell, these organelles convert nutrients into adenosine triphosphate (ATP), the energy currency that powers cellular activities.

Structure of mitochondria: A closer look

Mitochondria are unique among cellular organelles, distinguished by their double-membrane structure. The outer membrane encases the organelle, while the inner membrane folds into cristae, increasing the surface area for energy production.

This specialized architecture facilitates the efficient production of ATP through the process of oxidative phosphorylation, a testament to the organelle’s evolutionary origins from symbiotic bacteria.

Genetic blueprint of mitochondrial DNA (mtDNA)

An intriguing aspect of mitochondria is their possession of their own DNA (mtDNA), separate from the nuclear DNA found in the cell’s nucleus.

This mtDNA encodes essential proteins for the organelle’s energy-generating functions, highlighting mitochondria’s evolutionary ancestry as independent organisms.

The inheritance of mtDNA through the maternal line opens fascinating avenues for studying genetics, evolution, and hereditary diseases.

Role of mitochondria in health and disease

Mitochondria are central to more than just energy production; they are crucial in calcium signaling, apoptosis (programmed cell death), and the regulation of cellular metabolism.

Dysfunctions in mitochondrial operations can lead to a spectrum of diseases, collectively known as mitochondrial disorders, impacting organs and systems that require high energy, such as the brain, heart, and muscles.

Additionally, mitochondrial dysfunction is implicated in neurodegenerative diseases, metabolic syndromes, and the aging process.

Future of mitochondrial research

The ongoing research into mitochondrial biology holds promise for novel therapeutic strategies to combat mitochondrial diseases, enhance human health, and extend lifespan.

Scientists are exploring ways to manipulate mitochondrial functions, develop treatments for mitochondrial disorders, and even use mitochondrial DNA as a biomarker for certain diseases.

In summary, mitochondria, with their complex functions and critical role in cellular energy production, are key players in maintaining cellular and organismal health.

As research unfolds, the mysteries of these remarkable organelles continue to reveal new insights into their potential for treating diseases and enhancing human health, marking an exciting frontier in biological and medical sciences.

The full study was published in the journal Nature Cell Biology.


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