Molecular mechanisms of the endosomal removal of mitochondrial content

• Applicant: Professor David Pla Martin, Ph.D.
• Subject Area: Biogerontology and Geriatric Medicine ; Biochemistry ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445067265

The mtDNA is a small circular molecule present in multiple copies per cell and encoding essential subunits of the respiratory chain. Mutations in the mtDNA, are implicated in severe neuro-muscular diseases, contribute to metabolic rearrangements in certain cancers, and accumulate in various tissues as a hallmark of aging. Hence, maintaining mtDNA integrity is essential for cellular fitness. Mitophagy, the selective removal of damaged mitochondria, regulates organelle balance by eliminating dysfunctional mitochondria, including those carrying damaged mtDNA. Traditionally, mitochondria are targeted for degradation and engulfed in an autophagosome, which lately will fuse with a lysosome for degradation. However, this process lacks specificity for mitochondrial components, potentially compromising cellular function by removing functional parts of the organelle. The identification of highly specific mitochondrial quality control mechanisms has introduced a new paradigm, focusing on the selective removal of only ill-functional components. Recently, we discovered a novel mechanism for the removal of oxidated mtDNA. Under conditions of mtDNA replication stress, the mitochondrial genome separates from the mitochondrial network and becomes integrated into the cellular vesicular system. Here, the retromer complex, along with its core component VPS35, facilitates the extraction of mitochondrial components. Through a process reminiscent of mitochondrial-derived vesicles, mitochondrial matrix materials, including mtDNA, are transferred to endosomes-lysosomes for degradation. Intriguingly, the overexpression of VPS35 enhances quality control mechanisms and restores mitochondrial homeostasis, in a model with mtDNA damage, highlighting the pivotal role of the retromer complex as a master regulator in this pathway. Despite these advancements, the molecular players controlling the transfer of mtDNA to recycling organelles remain elusive. In this proposal, our objective is to elucidate the molecular control of the retromer-dependent quality control, both from the endosomal (objective 1) and mitochondrial perspective (objective 2). Thus, we aim to identify the proteins involved in recognizing mitochondrial cargo. Additionally, we will investigate how mitochondrial stress, including mtDNA replication stress and other mitochondrial stressors, influences the lysosomal function (objective 3). In conclusion, with this project, we aim to shed light on the molecular aspects of this newly identified path, with potential benefits to understanding mtDNA damage-associated diseases.

• DFG Programme: Research Grants