The Mitochondrial Lon Protease: Novel Functions off the Beaten Track?

Voos, Wolfgang; Pollecker, Karen

doi:10.3390/biom10020253

Cited by 36 publications

(29 citation statements)

References 91 publications

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“…5 ). A decreased level (fold change = 0.67; q = 4.20E-04) of mitochondrial Lon protease (LONP1), the major component of the mitochondrial protein quality control system under oxidative stress conditions [ 45 ], could have caused accumulation of misfolded proteins thus explaining this appearance. ER stress was enhanced in KO cells as revealed by dilated ER cisternae ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Knockout of PRDX6 induces mitochondrial dysfunction and cell cycle arrest at G2/M in HepG2 hepatocarcinoma cells

et al. 2020

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Peroxiredoxin 6 (PRDX6) has been associated with tumor progression and cancer metastasis. Its acting on phospholipid hydroperoxides and its phospholipase-A2 activity are unique among the peroxiredoxin family and add complexity to its action mechanisms. As a first step towards the study of PRDX6 involvement in cancer, we have constructed a human hepatocarcinoma HepG2 PRDX6 - /- cell line using the CRISPR/Cas9 technique and have characterized the cellular response to lack of PRDX6. Applying quantitative global and redox proteomics, flow cytometry, in vivo extracellular flow analysis, Western blot and electron microscopy, we have detected diminished respiratory capacity, downregulation of mitochondrial proteins and altered mitochondrial morphology. Autophagic vesicles were abundant while the unfolded protein response (UPR), HIF1A and NRF2 transcription factors were not activated, despite increased levels of p62/SQSTM1 and reactive oxygen species (ROS). Insulin receptor (INSR), 3-phosphoinositide-dependent protein kinase 1 (PDPK1), uptake of glucose and hexokinase-2 (HK2) decreased markedly while nucleotide biosynthesis, lipogenesis and synthesis of long chain polyunsaturated fatty acids (LC-PUFA) increased. 254 Cys-peptides belonging to 202 proteins underwent significant redox changes. PRDX6 knockout had an antiproliferative effect due to cell cycle arrest at G2/M transition, without signs of apoptosis. Loss of PLA2 may affect the levels of specific lipids altering lipid signaling pathways, while loss of peroxidase activity could induce redox changes at critical sensitive cysteine residues in key proteins. Oxidation of specific cysteines in Proliferating Cell Nuclear Antigen (PCNA) could interfere with entry into mitosis. The GSH/Glutaredoxin system was downregulated likely contributing to these redox changes. Altogether the data demonstrate that loss of PRDX6 slows down cell division and alters metabolism and mitochondrial function, so that cell survival depends on glycolysis to lactate for ATP production and on AMPK-independent autophagy to obtain building blocks for biosynthesis. PRDX6 is an important link in the chain of elements connecting redox homeostasis and proliferation.

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Section: Resultsmentioning

confidence: 99%

Knockout of PRDX6 induces mitochondrial dysfunction and cell cycle arrest at G2/M in HepG2 hepatocarcinoma cells

et al. 2020

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“…Inside the mitochondria, the protease Lon is a crucial regulator responsible for mitochondrial metabolism and hemostasis [ 134 , 135 ]. Owing to its chaperone activity, mitochondrial Lon controls mitochondrial protein quality, mitochondrial DNA (mtDNA) repair, and ROS production.…”

Section: Overview Of the Impact Of The Tme On Oral Sccmentioning

confidence: 99%

“…Owing to its chaperone activity, mitochondrial Lon controls mitochondrial protein quality, mitochondrial DNA (mtDNA) repair, and ROS production. Therefore, several studies have attempted to elucidate the critical role of mitochondrial Lon in tumorigenic activity, focusing on proliferation, antiapoptosis, and EMT [ 134 , 135 ]. Recent studies have revealed a novel connection between mitochondrial Lon and an immunosuppressive TME in oral cancer [ 136 , 137 ].…”

Section: Overview Of the Impact Of The Tme On Oral Sccmentioning

confidence: 99%

New Insights Into Oral Squamous Cell Carcinoma: From Clinical Aspects to Molecular Tumorigenesis

Chen

Hsiao

Chang

et al. 2021

IJMS

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Oral squamous cell carcinoma (SCC) is a prevalent malignant disease worldwide, especially so in Taiwan. Early- or even preclinical-stage detection is critical for reducing morbidity and mortality from oral SCC. Epidemiological and genome association studies are useful for identifying clinicopathological risk factors for preventive, diagnostic, and therapeutic approaches of oral SCC. For advanced oral SCC, effective treatments are critical to prolonging survival and enhancing quality of life. As oral SCC is characteristic of regional invasion with lymph node metastases, understanding the aggressive features of oral SCC, particularly in lymphangiogenesis, is essential for determining effective treatments. Emerging evidence has demonstrated that the tumor microenvironment (TME) plays a pivotal role in tumor growth, invasion, and metastases. Recent clinical successes in immune checkpoint inhibitors either alone or combined with chemotherapy have also supported the therapeutic value of immunotherapy in oral SCC. This review summarizes critical advances in basic knowledge of oral SCC from the perspective of clinicopathological risk factors, molecular tumorigenesis, and the TME. We also highlight our recent investigations on the microbiome, genome association studies, lymphangiogenesis, and immunomodulation in oral SCC. This review may provide new insights for oral SCC treatment by systematically interpreting emerging evidence from various preclinical and clinical studies.

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“…For this purpose, mitochondria are equipped with a unique set of proteases dedicated to specific subcompartments. Members of the Lon AAA + -protease fusion family reside in the matrix and degrade denatured or oxidized proteins [ 21 ]. Working in parallel to Lon, ClpP is another matrix-resident ATP-dependent protease which functions together with a AAA + chaperone protein, ClpX [ 22 ].…”

Section: Introduction—modes Of Mitochondrial Protein Quality Contrmentioning

confidence: 99%

Ubiquitination of Intramitochondrial Proteins: Implications for Metabolic Adaptability

2020

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Mitochondria are constantly subjected to stressful conditions due to their unique physiology and organization. The resulting damage leads to mitochondrial dysfunction, which underlies many pathophysiological conditions. Hence, constant surveillance is required to closely monitor mitochondrial health for sound maintenance of cellular metabolism and thus, for viability. In addition to internal mitochondrial chaperones and proteases, mitochondrial health is also governed by host cell protein quality control systems. The ubiquitin-proteasome system (UPS) and autophagy constitute the main pathways for removal of damaged or superfluous proteins in the cytosol, nucleus, and from certain organelles such as the Endoplasmic Reticulum (ER) and mitochondria. Although stress-induced ubiquitin-dependent degradation of mitochondrial outer membrane proteins has been widely studied, mechanisms of intramitochondrial protein ubiquitination has remained largely elusive due to the predominantly cytosolic nature of UPS components, separated from internal mitochondrial proteins by a double membrane. However, recent research has illuminated examples of intramitochondrial protein ubiquitination pathways and highlighted their importance under basal and stressful conditions. Owing to the dependence of mitochondria on the error-prone process of protein import from the cytosol, it is imperative that the cell eliminate any accumulated proteins in the event of mitochondrial protein import deficiency. Apparently, a significant portion of this activity involves ubiquitination in one way or another. In the present review article, following a brief introduction to mitochondrial protein quality control mechanisms, we discuss our recent understanding of intramitochondrial protein ubiquitination, its importance for basal function of mitochondria, metabolic implications, and possible therapeutic applications.

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The Mitochondrial Lon Protease: Novel Functions off the Beaten Track?

Cited by 36 publications

References 91 publications

Knockout of PRDX6 induces mitochondrial dysfunction and cell cycle arrest at G2/M in HepG2 hepatocarcinoma cells

Knockout of PRDX6 induces mitochondrial dysfunction and cell cycle arrest at G2/M in HepG2 hepatocarcinoma cells

New Insights Into Oral Squamous Cell Carcinoma: From Clinical Aspects to Molecular Tumorigenesis

Ubiquitination of Intramitochondrial Proteins: Implications for Metabolic Adaptability

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