PINK1

Researchers uncovered the mechanistic details behind how several proteins interact to help cells recognize and remove damaged mitochondria. Optineurin (OPTN) and its interactions are needed to provide a contact site for another protein, Tank-binding kinase 1 (TBK1), during this process. The OPTN-TBK1 relationship is necessary for these mitochondria to be recognized and eliminated from the cell. This mechanism may have relevance for developing drugs to treat Parkinson's disease. Autophagy is a process used by cells as a recycling system to transport and break down organelles and other cytosolic components, which become enveloped in a membrane called the autophagosome (Fig 1). When this involves the removal of damaged mitochondria, commonly called the "powerhouse" of the cell, it is known as mitophagy. In a recent article published in The EMBO Journal, a team led by researchers at Tokyo Medical and Dental University (TMDU) elucidated the molecular details of how an enzyme called Tank-binding kinase 1 (TBK1) participates in a disease-relevant mitophagy mechanism. Although autophagy has been characterized as a more general process meant to degrade and clear various cellular components, recent data have suggested that certain pathways are specifically involved in the autophagy of particular organelle types that are damaged or no longer needed. The researchers became interested in mitophagy mediated by molecules called PINK1 and Parkin, as they are proteins that have been pathologically linked to Parkinson's disease. "Mitophagy-related defects have been directly implicated in the neurodegeneration observed in Parkinson's disease patients," says Koji Yamano, lead author of the study. "Normally, PINK1 and Parkin work together to mark damaged mitochondria for removal by adding a chain of molecules called ubiquitin. This mark allows proteins called autophagy adaptors to associate with the mitochondria and bring in the autophagy machinery for autophagosome development." Although TBK1 is known to participate in PINK1/Parkin-mediated mitophagy, a detailed mechanism how it activates remained unclear. Using various molecular biology techniques, the team found that deleting the gene encoding TBK1 prevented association of an autophagy adaptor called optineurin (OPTN) during Parkin-mediated mitophagy (Fig 2). Additionally, deleting the OPTN gene prevented autophosphorylation of TBK1, which is necessary for it to function. Further work suggested that the interactions between OPTN and ubiquitin, as well as between OPTN and the developing autophagosome, were all needed for OPTN and TBK1 to come together at the contact site between damaged mitochondria and the pre-autophagosome membrane. Without this contact site, TBK1 autophosphorylation could not occur. The researchers also generated molecules called monobodies in their lab that could specifically bind OPTN and inhibit its physical interactions. The monobodies prevented OPTN accumulation at the mitophagy contact sites (Fig 3A). This subsequently blocked TBK1 activation (Fig 3B) and thereby mitochondrial degradation. These experiments further emphasized the importance of the OPTN-TBK1 relationship to support proper mitophagy. "Because PINK1 and Parkin are critical contributors to the molecular basis of Parkinson's disease, understanding the mechanistic details related to the mitophagy process mediated by these molecules is very important," explains Yamano. This study demonstrates a positive and reciprocal relationship between OPTN and TBK1 that is necessary for autophagosomes to begin forming on damaged mitochondria. The impactful finding may lead to the development of novel drugs to treat Parkinson's disease.

Researchers have shown that a protein called HKDC1 is a new target of another protein, TFEB, and plays key roles in maintaining the stability of both mitochondria and lysosomes. HKDC1 is essential for mitophagy to remove damaged mitochondria, and mediates mitochondria-lysosome contact, which is critical for lysosomal repair. The role of HKDC1 in maintaining the stability of these organelles counteracts cellular senescence, revealing HKDC1 as a potential therapeutic target for age-related diseases. Just as healthy organs are vital to our well-being, healthy organelles are vital to the proper functioning of the cell. These subcellular structures carry out specific jobs within the cell, for example, mitochondria power the cell and lysosomes keep the cell tidy. Although damage to these two organelles has been linked to aging, cellular senescence, and many diseases, the regulation and maintenance of these organelles has remained poorly understood. Now, researchers at Osaka University have identified a protein, HKDC1, that plays a key role in maintaining these two organelles, thereby acting to prevent cellular aging. There was evidence that a protein called TFEB is involved in maintaining the function of both organelles, but no targets of this protein were known. By comparing all the genes of the cell that are active under particular conditions, and by using a method called chromatin immunoprecipitation, which can identify the DNA targets of proteins, the team were the first to show that the gene encoding HKDC1 is a direct target of TFEB, and that HKDC1 becomes upregulated under conditions of mitochondrial or lysosomal stress. One way that mitochondria are protected from damage is through the process of "mitophagy," the controlled removal of damaged mitochondria. There are various mitophagy pathways, and the most well-characterized of these depends on proteins called PINK1 and Parkin. "We observed that HKDC1 co-localizes with a protein called TOM20, which is located in the outer membrane of the mitochondria," explains lead author Mengying Cui, "and through our experiments, we found that HKDC1, and its interaction with TOM20, are critical for PINK1/Parkin-dependent mitophagy." So, put simply, HKDC1 is brought in by TFEB to help take out the mitochondrial trash. But what about lysosomes? Well, TFEB and KHDC1 are key players here, too. Reducing HKDC1 in the cell was shown to interfere with lysosomal repair, indicating that HKDC1 and TFEB help lysosomes to recover from damage. "HKDC1 is localized to the mitochondria, right? Well, this turns out to also be critical for the process of lysosomal repair," explains senior author Shuhei Nakamura. "You see, lysosomes and mitochondria contact each other via proteins called VDACs. Specifically, HKDC1 is responsible for interacting with the VDACs; this protein is essential for mitochondria-lysosome contact, and thus, lysosomal repair." These two diverse functions of HKDC1, with key roles in both the lysosome and the mitochondria, help to prevent cellular senescence by simultaneously maintaining the stability of these two organelles. As dysfunction of these organelles is linked to aging and age-related diseases, this discovery opens new avenues for therapeutic approaches to these diseases.

CAMBRIDGE, England, Oct. 10, 2023 /PRNewswire/ -- Mission Therapeutics ("Mission"), a clinical-stage biotech company developing first-in-class therapeutics targeting mitophagy, today announces that its Chief Scientific Officer, Dr Paul Thompson, will give an oral presentation on its experimental drug candidate MTX325 at the 15th Annual Michael J. Fox Foundation's Parkinson's Disease Therapeutics Conference on October 19, 2023, in New York. Dr Thompson will participate in the session titled 'Advances in Emerging Targets and Therapeutic Development' where he will discuss Mission's data demonstrating development of USP30 inhibitors for the treatment of Parkinson's Disease (PD). As the world's largest nonprofit funder of Parkinson's research, The Michael J. Fox Foundation (MJFF) is dedicated to accelerating a cure for Parkinson's Disease and improved therapies for those living with the condition today. The annual Michael J. Fox Foundation's Parkinson's Disease Therapeutics Conference brings together 300 research and business development professionals from both academia and industry and showcases the most exciting and innovative research from MJFF's research portfolio, and serves as a unique platform for field leaders to share new and unpublished results. Dr Paul Thompson, Ph.D., Chief Science Officer of Mission Therapeutics, commented: "We look forward to presenting our recent findings on USP30 inhibition for the treatment of Parkinson's Disease at this prestigious conference. The Michael J. Fox Foundation shares our mission of unlocking the complex biology of Parkinson's Disease to slow disease progression and improve patient lives with the development of the next generation of treatments." Mission Therapeutics is a world leader in discovering and developing novel therapeutics which promote the removal of dysfunctional mitochondria to maintain cell health and function. A major unmet need for Parkinson's Disease patients is a treatment that slows or prevents the progression of disease. Mitochondrial dysfunction is considered a key pathophysiological driver of Parkinson's Disease (PD) and several disease-associated gene mutations affect proteins involved in a dysfunctional mitochondria ubiquitin-dependent clearance mechanism known as mitophagy, including PINK1 and the ubiquitin E3 ligase, Parkin. USP30 is a deubiquitylating (DUB) enzyme uniquely localized to the mitochondria that removes ubiquitin groups and is a negative regulator of the PINK1/Parkin pathway and mitophagy. Inhibiting USP30 has therefore been proposed as a therapeutic mechanism for protecting vulnerable dopamine-producing neurons in PD. Mission Therapeutics is currently developing two DUB inhibitors: MTX325 (targeting the CNS) and MTX652 (peripheral) which can potentially be used to treat any disease driven by mitochondrial dysfunction. About Mission Therapeutics Mission Therapeutics is a world leader in discovering and developing novel therapeutics which promote the removal of dysfunctional mitochondria, promoting cell health and function. Mitochondria are energy producing organelles which require lifetime quality control through a ubiquitin-mediated clearance mechanism known as mitophagy. In certain situations, such as cellular stress, cell injury, and/or defects of the mitophagy process, the mitochondria can become dysfunctional and damaging to the cell, leading to reduced energy production, oxidative stress, inflammation and potentially cell death. Dysfunctional mitochondria are significant drivers of disease pathophysiology in acute kidney injury (AKI), Parkinson's Disease (PD), heart failure, Duchenne's Muscular Dystrophy, IPF, mitochondrial diseases and Alzheimer's. USP30 is a deubiquitylating enzyme that constantly removes ubiquitin from mitochondria, providing a potential brake on clearance of dysfunctional mitochondria. Mission is currently developing two small molecule drugs, MTX652 (peripheral) and MTX325 (targeting the CNS) which, through inhibition of the mitochondrial DUB enzyme USP30, will promote clearance of dysfunctional mitochondria – consequently improving overall cellular health. Mission's USP30 inhibitors MTX652 and MTX325 could potentially be used to treat any disease or condition driven by mitochondrial dysfunction. Mission has completed its first Phase I clinical study with MTX652, demonstrating a highly encouraging safety, tolerability and pharmacokinetic profile. A Phase II trial of MTX652 in patients at risk of acute kidney injury following cardiac surgery is planned to start in Q1 2024. A Phase I trial of MTX325 in healthy volunteers and patients with PD is planned to start in Q1 2024. Mission is backed by blue chip investors including Pfizer Venture Investments, Sofinnova Partners, Roche Venture Fund, SR One, IP Group and Rosetta Capital. SOURCE Mission Therapeutics