Certainly! Here’s a paraphrased version of the article, maintaining the same core information and structured in HTML format with headings and about seven paragraphs:
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<p>Mitochondria, often described as the cell's powerhouses, contain distinctive DNA that can undergo mutations linked to various diseases, leading to energy deficiency in cells. Recently, researchers have discovered a groundbreaking molecule capable of reversing the detrimental effects of prevalent mutations associated with these genetic disorders.</p>
<p>"These mutations can lead to a variety of diseases for which we currently lack effective treatments," noted <a href="https://cesne.biologia.unipd.it/research-groups/carlo-viscomi/" target="_blank"><u>Carlo Viscomi</u></a>, an associate professor at the University of Padova's Department of Biomedical Science and Padua Neuroscience Center in Italy.</p>
<p>"This paper represents a significant breakthrough," Viscomi remarked, despite not being directly involved in the research. "It opens up incredible possibilities for addressing these conditions." However, he mentioned a limitation in the study: it did not evaluate the molecule's effectiveness in living organisms. Following this research, scientists have developed a similar molecule that is <a href="https://www.pretzeltx.com/pretzel-therapeutics-initiates-phase-1-clinical-study-evaluating-px578-lead-therapeutic-in-its-bioenergetics-restoration-franchise/" target="_blank"><u>now undergoing human trials</u></a> led by Pretzel Therapeutics, where some paper authors are involved.</p>
<h2 id="extremely-variable-diseases">Highly Variable Diseases</h2>
<p>Published in April in <a href="https://www.nature.com/articles/s41586-025-08856-9" target="_blank"><u>Nature</u></a>, the study concentrated on polymerase gamma-related diseases, or <a href="https://www.livescience.com/health/genetics/polg-diseases-rare-genetic-conditions-that-starve-cells-of-energy-and-afflicted-the-prince-of-luxembourg" target="_blank"><u>POLG-related diseases</u></a>. These rare, genetic conditions affect an estimated 1 in 10,000 individuals globally, stemming from mutations in the POLG gene, essential for mitochondrial function.</p>
<p>The DNA within mitochondria requires replication as new mitochondria form, and it also needs repair due to damage from factors such as oxidative stress. However, approximately <a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC9289853/" target="_blank"><u>300 different mutations</u></a> in the POLG gene disrupt this replication and repair process, impairing the associated enzyme: polymerase gamma (POLG).</p>
<p>These mutations lead to the accumulation of harmful alterations in mitochondrial DNA, eventually resulting in various symptoms that differ greatly among individuals. "The variability is immense," commented Viscomi. Conditions like <a href="https://www.ncbi.nlm.nih.gov/books/NBK540966/" target="_blank"><u>Alpers-Huttenlocher syndrome</u></a>, one of the most critical POLG disorders, typically manifests symptoms between ages 2 and 4, leading to severe complications and often resulting in death within four years.</p>
<h2 id="hunt-for-a-promising-drug">Searching for a Promising Drug</h2>
<p>The researchers hypothesized that a drug enhancing healthy POLG activity could also support mutant versions. They screened a library of 270,000 compounds to identify how they influenced healthy POLG activity. This process yielded a candidate molecule, which they chemically modified for improved efficacy, naming the refined version PZL-A.</p>
<p>The study emphasized just four POLG mutations rather than the entire set of 300, focusing on those present in about 70% of affected individuals. Using cryogenic electron microscopy, they detailed how PZL-A interacted with both healthy POLG and the targeted mutations. PZL-A binds in a specific pocket that remains unaffected by common disease-causing mutations, ultimately enhancing protein stability and DNA repair capacity.</p>
<p>Initial experiments demonstrated that cells treated with PZL-A recovered lost mitochondrial DNA significantly faster than untreated cells, occasionally matching the rate of healthy POLG. The research team intends to evaluate additional POLG mutations and is already testing a similar compound in clinical trials.</p>
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