Mitochondrial CLPP2 Assists Coordination and Homeostasis of Respiratory Complexes

Petereit, Jakob; Duncan, Owen; Murcha, Monika W.; Fenske, Ricarda; Cincu, Emilia; Cahn, Jonathan; Pružinská, Adriana; Ivanova, Aneta; Kollipara, Laxmikanth; Wortelkamp, Stefanie; Sickmann, Albert; Lee, Jiwon; Lister, Ryan; Millar, A. Harvey; Huang, Shaobai

doi:10.1104/pp.20.00136

Cited by 31 publications

(21 citation statements)

References 82 publications

(109 reference statements)

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“…Most of the substrates, including components of the pyruvate dehydrogenase complex, the tricarboxylic acid (TCA) cycle, and the respiratory chain, are involved in mitochondrial energy metabolism. Among these, there are components of the N-module of respiratory complex I which were subsequently also identified in mammals and the plant Arabidopsis thaliana ( Szczepanowska et al, 2016 ; Petereit et al, 2020 ) suggesting at least a partial conserved role of CLPXP in pathways involved in cellular energy metabolism.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Ablation of the Catalytic AMPK α-Subunit SNF1 and Mitochondrial Matrix Protease CLPP Results in Pronounced Lifespan Extension

Heinz

Krotova

Hamann

et al. 2021

Front. Cell Dev. Biol.

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Organismic aging is known to be controlled by genetic and environmental traits. Pathways involved in the control of cellular metabolism play a crucial role. Previously, we identified a role of PaCLPP, a mitochondrial matrix protease, in the control of the mitochondrial energy metabolism, aging, and lifespan of the fungal aging model Podospora anserina. Most surprisingly, we made the counterintuitive observation that the ablation of this component of the mitochondrial quality control network leads to lifespan extension. In the current study, we investigated the role of energy metabolism of P. anserina. An age-dependent metabolome analysis of the wild type and a PaClpP deletion strain verified differences and changes of various metabolites in cultures of the PaClpP mutant and the wild type. Based on these data, we generated and analyzed a PaSnf1 deletion mutant and a ΔPaSnf1/ΔPaClpP double mutant. In both mutants PaSNF1, the catalytic α-subunit of AMP-activated protein kinase (AMPK) is ablated. PaSNF1 was found to be required for the development of fruiting bodies and ascospores and the progeny of sexual reproduction of this ascomycete and impact mitochondrial dynamics and autophagy. Most interestingly, while the single PaSnf1 deletion mutant is characterized by a slight lifespan increase, simultaneous deletion of PaSnf1 and PaClpP leads to a pronounced lifespan extension. This synergistic effect is strongly reinforced in the presence of the mating-type “minus”-linked allele of the rmp1 gene. Compared to the wild type, culture temperature of 35°C instead of the standard laboratory temperature of 27°C leads to a short-lived phenotype of the ΔPaSnf1/ΔPaClpP double mutant. Overall, our study provides novel evidence for complex interactions of different molecular pathways involved in mitochondrial quality control, gene expression, and energy metabolism in the control of organismic aging.

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Section: Introductionmentioning

confidence: 99%

Simultaneous Ablation of the Catalytic AMPK α-Subunit SNF1 and Mitochondrial Matrix Protease CLPP Results in Pronounced Lifespan Extension

Heinz

Krotova

Hamann

et al. 2021

Front. Cell Dev. Biol.

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“…100 µg frozen mitochondrial proteins were precipitated in 100% acetone for 24 hours at - 20°C and the pellets were washed with acetone for three times. Samples were alkylated, trypsin digested, desalted and cleaned as previously described (Petereit et al, 2020). Samples were loaded onto an AdvanceBio Peptide Map column (2.1 × 250 mm, 2.7 μm particle size; part number 651750-902, Agilent), using an Agilent 1290 Infinity II LC System coupled to an Agilent 6495 Triple Quadrupole MS.…”

Section: Methodsmentioning

confidence: 99%

The mitochondrial pyruvate carrier (MPC) complex is one of three pyruvate-supplying pathways that sustain Arabidopsis respiratory metabolism

Lee

Millar

2021

Preprint

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Malate oxidation by plant mitochondria enables the generation of both oxaloacetate (OAA) and pyruvate for tricarboxylic acid (TCA) cycle function, potentially eliminating the need for pyruvate transport into mitochondria in plants. Here we show that the absence of the mitochondrial pyruvate carrier 1 (MPC1) causes the co-commitment loss of its orthologs, MPC3/MPC4, and eliminates pyruvate transport into Arabidopsis mitochondria, proving it is essential for MPC complex function. While the loss of either MPC or mitochondrial pyruvate-generating NAD-malic enzyme (NAD-ME) did not cause vegetative phenotypes, the lack of both reduced plant growth and caused an increase in cellular pyruvate levels, indicating a block in respiratory metabolism, and elevated the levels of branched-chain amino acids at night, a sign of alterative substrate provision for respiration. 13C-pyruvate feeding of leaves lacking MPC showed metabolic homeostasis were largely maintained except for alanine and glutamate, indicating that transamination contributes to restoration of the metabolic network to an operating equilibrium by delivering pyruvate independently of MPC into the matrix. Inhibition of alanine aminotransferases (AlaAT) when MPC1 is absent resulted in extremely retarded phenotypes in Arabidopsis, suggesting all pyruvate-supplying enzymes work synergistically to support the TCA cycle for sustained plant growth.

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“…Some overlapping proteins were later also found in mammals and Arabidopsis thaliana . In particular, components of the N-module of complex I of the respiratory chain appear to be conserved substrates of CLPXP [ 58 , 59 , 60 ].…”

Section: Repair and Degradation Of Cellular Componentsmentioning

confidence: 99%

A Network of Pathways Controlling Cellular Homeostasis Affects the Onset of Senescence in Podospora anserina

Osiewacz

Schürmanns

2021

JoF

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Research on Podospora anserina unraveled a network of molecular pathways affecting biological aging. In particular, a number of pathways active in the control of mitochondria were identified on different levels. A long-known key process active during aging of P. anserina is the age-related reorganization of the mitochondrial DNA (mtDNA). Mechanisms involved in the stabilization of the mtDNA lead to lifespan extension. Another critical issue is to balance mitochondrial levels of reactive oxygen species (ROS). This is important because ROS are essential signaling molecules, but at increased levels cause molecular damage. At a higher level of the network, mechanisms are active in the repair of damaged compounds. However, if damage passes critical limits, the corresponding pathways are overwhelmed and impaired molecules as well as those present in excess are degraded by specific enzymes or via different forms of autophagy. Subsequently, degraded units need to be replaced by novel functional ones. The corresponding processes are dependent on the availability of intact genetic information. Although a number of different pathways involved in the control of cellular homeostasis were uncovered in the past, certainly many more exist. In addition, the signaling pathways involved in the control and coordination of the underlying pathways are only initially understood. In some cases, like the induction of autophagy, ROS are active. Additionally, sensing and signaling the energetic status of the organism plays a key role. The precise mechanisms involved are elusive and remain to be elucidated.

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Mitochondrial CLPP2 Assists Coordination and Homeostasis of Respiratory Complexes

Cited by 31 publications

References 82 publications

Simultaneous Ablation of the Catalytic AMPK α-Subunit SNF1 and Mitochondrial Matrix Protease CLPP Results in Pronounced Lifespan Extension

Simultaneous Ablation of the Catalytic AMPK α-Subunit SNF1 and Mitochondrial Matrix Protease CLPP Results in Pronounced Lifespan Extension

The mitochondrial pyruvate carrier (MPC) complex is one of three pyruvate-supplying pathways that sustain Arabidopsis respiratory metabolism

A Network of Pathways Controlling Cellular Homeostasis Affects the Onset of Senescence in Podospora anserina

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