bims-mitpro 2023-09-03 papers

bims-mitpro

Biomed News

on Mitochondrial Proteostasis

Issue of 2023‒09‒03
six papers selected by
Andreas Kohler

Mitophagy-promoting agents and their ability to promote healthy-aging.
Triaging of ⍺-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.
Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.
Mitochondrial Microproteins: Critical Regulators of Protein Import, Energy Production, Stress Response Pathways, and Programmed Cell Death.
Mitophagy: from the dark into the spotlight.
Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis.

Biochem Soc Trans. 2023 Aug 31. pii: BST20221363. [Epub ahead of print]

Mitophagy-promoting agents and their ability to promote healthy-aging.

Vijigisha Srivastava, Einav Gross.

  The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.

Keywords:  aging; lifespan; mitochondria; mitochondrial autophagy; mitochondrial biogenesis; mitophagy

DOI:  https://doi.org/10.1042/BST20221363
bioRxiv. 2023 Aug 17. pii: 2023.08.16.553624. [Epub ahead of print]

Triaging of ⍺-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.

Gayathri Muthukumar, Taylor A Stevens, Alison J Inglis, Theodore K Esantsi, Reuben A Saunders, Fabian Schulte, Rebecca M Voorhees, Alina Guna, Jonathan S Weissman.

Mitochondrial outer membrane ⍺-helical proteins play critical roles in mitochondrial-cytoplasmic communication, but the rules governing the targeting and insertion of these biophysically diverse substrates remain unknown. Here, we first defined the complement of required mammalian biogenesis machinery through genome-wide CRISPRi screens using topologically distinct membrane proteins. Systematic analysis of nine identified factors across 21 diverse ⍺-helical substrates reveals that these components are organized into distinct targeting pathways which act on substrates based on their topology. NAC is required for efficient targeting of polytopic proteins whereas signal-anchored proteins require TTC1, a novel cytosolic chaperone which physically engages substrates. Biochemical and mutational studies reveal that TTC1 employs a conserved TPR domain and a hydrophobic groove in its C-terminal domain to support substrate solubilization and insertion into mitochondria. Thus, targeting of diverse mitochondrial membrane proteins is achieved through topological triaging in the cytosol using principles with similarities to ER membrane protein biogenesis systems.

DOI: https://doi.org/10.1101/2023.08.16.553624
Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302360120

Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.

Laura M de Smalen, Anastasiya Börsch, Aurel B Leuchtmann, Jonathan F Gill, Danilo Ritz, Mihaela Zavolan, Christoph Handschin.

  Sarcopenia, the age-related loss of skeletal muscle mass and function, can dramatically impinge on quality of life and mortality. While mitochondrial dysfunction and imbalanced proteostasis are recognized as hallmarks of sarcopenia, the regulatory and functional link between these processes is underappreciated and unresolved. We therefore investigated how mitochondrial proteostasis, a crucial process that coordinates the expression of nuclear- and mitochondrial-encoded mitochondrial proteins with supercomplex formation and respiratory activity, is affected in skeletal muscle aging. Intriguingly, a robust mitochondrial translation impairment was observed in sarcopenic muscle, which is regulated by the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) with the estrogen-related receptor α (ERRα). Exercise, a potent inducer of PGC-1α activity, rectifies age-related reduction in mitochondrial translation, in conjunction with quality control pathways. These results highlight the importance of mitochondrial proteostasis in muscle aging, and elucidate regulatory interactions that underlie the powerful benefits of physical activity in this context.

Keywords:  aging; mitochondria; proteostasis; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2302360120
Am J Physiol Cell Physiol. 2023 Aug 29.

Mitochondrial Microproteins: Critical Regulators of Protein Import, Energy Production, Stress Response Pathways, and Programmed Cell Death.

Michael L Kamradt, Catherine A Makarewich.

  Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria (TOMM complex, TIMM complex, OXPHOS complexes, mitoribosomes). These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines; they also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.

Keywords:  cell stress; microproteins; mitochondria; mitochondrial protein import; oxidative phosphorylation

DOI:  https://doi.org/10.1152/ajpcell.00189.2023
Mol Plant. 2023 Aug 31. pii: S1674-2052(23)00250-2. [Epub ahead of print]

Mitophagy: from the dark into the spotlight.

Vivian Schmitt, Olivier Van Aken.

Despite the generally placid appearance of plants, many dynamic processes take place inside a plant cell. One such process that has garnered attention in recent years is termed 'autophagy'. While originally discovered in yeast, our understanding of autophagy in plants has improved significantly. Autophagy is considered a cellular recycling system in which cellular components or even entire organelles can be encapsulated by a membrane structure (autophagosome) and then transported to the vacuole (in plants) for degradation and re-use. One example of components degraded by autophagy are the mitochondria ('mitophagy'). Only a few years ago there was almost no information about plant mitophagy available, but lately several important studies have been published. A recent study identified an ATG8-FLZ-SnRK1 regulatory axis that connects carbon starvation signaling to mitophagy. In this Spotlight article, we focus on the function of mitochondrial FLZ proteins and SnRK1, and discuss them in context of current knowledge on the regulation of mitophagy in plants.

DOI: https://doi.org/10.1016/j.molp.2023.08.015
Ecotoxicol Environ Saf. 2023 Aug 28. pii: S0147-6513(23)00913-2. [Epub ahead of print]264 115409

Mitochondrial oxidative stress regulates LonP1-TDP-43 pathway and rises mitochondrial damage in carbon tetrachloride-induced liver fibrosis.

Shulin Shan, Zhidan Liu, Shuai Wang, Zhaoxiong Liu, Shihua Chao, Cuiqin Zhang, Ming Li, Fuyong Song.

  Carbon tetrachloride (CCl4)-mediated liver damage has been well recognized, but the sources and mechanisms of mitochondrial damage during this progress still remain poorly understood. Accumulating evidence has revealed that LonP1-TDP-43 pathway affect proper mitochondrial integrity and function in neurodegenerative diseases. The current study aims to investigate whether mitochondrial oxidative stress regulate LonP1-TDP-43 pathway and the possible roles of this pathway in CCl4-driven liver fibrosis. We found that TDP-43 interacted with LonP1 in chronic CCl4 exposure-induced hepatic fibrogenesis. Moreover, CCl4 led to deficiency of LonP1 and excessive accumulation of TDP-43 on mitochondria. Particularly, the gene correlation analysis for liver fibrosis patients RNA sequencing (RNA-seq) results (GSE159676) showed an obvious negative correlation between LonP1 and TDP-43. By contrast, MitoQ enhanced the occurrence of mitochondrial unfolded protein response (mtUPR), especially the activation of LonP1 after CCl4 treatment. Importantly, mitochondrial antioxidant also promoted the degradation of TDP-43 and alleviated mitochondrial damage. In addition, our results showed that CCl4 induced the release of mitochondrial DNA (mtDNA) and effectively elevated cGAS-STING-mediated immune response, which can be inhibited by MitoQ. Finally, MitoQ prevented CCl4-induced liver fibrosis. Together, our study revealed that LonP1-TDP-43 pathway mediated by mitochondrial oxidative stress participated in the progress of CCl4-drived liver fibrosis. Therefore, mitigating or reversing mitochondrial damage through targeting LonP1-TDP-43 pathway may serve as a promising therapeutic strategy for CCl4 exposure-induced liver diseases.

Keywords:  Liver fibrosis; LonP1; Mitochondrial dysfunction; TDP-43

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115409