DISCUSSION
To cope with energetically challenging conditions, plants activate strategic mechanisms of organelle disassembly, which generally culminate in a senescence-induced response. During both developmental and stress-induced senescence, chloroplast proteins are massively degraded, and the amino acids released can be either remobilized for other tissues or used as respiratory substrates (Araujo et al., 2011, Watanabe et al., 2013, Hildebrandt et al., 2015; Chrobok et al., 2016). It is well known that chloroplasts contain their own proteolytic machinery, comprising several types of proteases that operate in their protein quality control (Buet et al., 2019). This fact aside, recent studies have reported the existence of extra-plastidial pathways for chloroplast turnover (Otegui 2017; Izumi and Nakamura, 2018; Woodson 2022). Three main extra-plastidic processes involved in the degradation of chloroplasts were identified: autophagy (Ishida et al., 2008; Wada et al., 2009), SAVs (Otegui et al., 2005; Martínez et al., 2008), and CV (Wang and Blumwald, 2014). It remains unknown, however, how these distinct pathways are regulated and under which molecular hierarchy they ensure proper chloroplast turnover. We previously suggested that CV might function as a compensatory mechanism contributing to the sensitive phenotype of atg mutants under carbon starvation (Barros et al., 2017). Here, we provide additional experimental evidence of the importance of CV and autophagy pathways for both metabolic responses and chloroplast remodeling under extended darkness.
We first investigated the effects of the disruption of CV alone, on plant tolerance to extended darkness. Thus, we focused on phenotypic and metabolic characterization of previously described mutant lines exhibiting deficient expression of the CV gene (Wang and Blumwald, 2014). Accordingly, we verified that WT and amircv-1and amircv-2 plants displayed similar phenotypes under conditions of extended darkness (Fig. 2). However, the reduced protein content coupled with an elevated total free amino acid level after 3d of darkness indicates that mechanisms of protein turnover are more rapidly induced in the amircv mutants (Fig. 3). Furthermore, minor metabolic differences were observed between the amircv mutants and WT plants throughout the darkness treatment (Fig. 3 and 6). Additionally, the accumulation of amino acids was not correlated with differential activation of alternative respiration pathways in theamircv lines (Fig. 4). Collectively, these findings suggest that the altered protein response observed in the amircv mutants does not trigger significant effects on energetic metabolism.
It was previously demonstrated that silencing CV resulted in increased chloroplast stability, whereas CV overexpression led to chloroplast degradation by destabilizing the photosynthetic apparatus during abiotic stress (Wang and Blumwald, 2014; Sade et al., 2018; Ahouvi et al., 2022; Yu et al., 2022). By contrast, plants with enhanced autophagy were fitter and displayed enhanced tolerance to oxidative stress (Minina et al., 2018). Autophagy is a versatile mechanism of chloroplast degradation since it mediates the turnover of piecemeal stroma components and the degradation of entire chloroplasts by the chlorophagy mechanism (Izumi and Nakamura, 2018). Experimental evidence has suggested that the selective degradation of stromal proteins mediated by autophagy, the RCB pathway, is preferentially activated to provide amino acids in energy-starved plants (Hirota et al., 2018; Izumi et al., 2019). Taken together, the data described above, coupled with our results, suggest that autophagy is more likely to operate as a pro-survival mechanism by the turnover of stromal components under starvation conditions, while CV leads to the widespread degradation of chloroplasts under specific abiotic stress conditions. Additionally, our previous study indicated a higher activation of the CV pathway inatg mutants submitted to extended darkness (Barros et al., 2017). Therefore, it is tempting to suggest that autophagy operates as a primary chloroplast degradation pathway, while CV is most likely a complementary mechanism activated in the absence of autophagy. By contrast, a recent study revealed that CV‐silenced tomato plants display stable chloroplast structure, ROS control, and delayed senescence in response to extended darkness (Yu et al., 2022). Therefore, these results open new questions regarding possibly contrasting roles of CV in metabolic reprogramming in different plant species under starvation conditions.
To unravel how these pathways modulate chloroplast turnover and stress-induced senescence response, we further characterized double mutants for both CV and autophagy pathways. Surprisingly, under extended darkness, these amircv1xatg5 mutants displayed an early senescence response accompanied by a reduction of chlorophyll levels, resembling the atg5 single mutant phenotype (Fig. 5). The metabolic analysis also demonstrated that tCV deficiency alone only resulted in minor effects on metabolic reprogramming, whereas the disruption of both autophagy and CV triggered similar effects as deficiency inatg alone(Fig. 6 and 7). Nevertheless, levels of specific amino acids differed between amircv1xatg5 and atg5mutants. The amircv1xatg5 double mutants displayed more reduced levels of arginine, aspartate, glutamate, isoleucine, serine and valine after 10d of darkness compared to the atg5 mutants (Fig. 6). Glutamine, glutamate, asparagine, aspartate, and their derivatives have been long documented to be key compounds of nitrogen metabolism (Masclaux-Daubresse et al., 2006; Gaufichon et al., 2016). The fact that the amircv1xatg5 mutant displayed reduced levels of arginine, aspartate and glutamate suggests a possible impairment of N remobilization pathways in the amircv1xatg5 mutants. Interestingly, the link between CV and N assimilation was previously observed in rice CV mutants under water stress (Sade et al., 2018). Under this condition, RNAiOsCV plants were characterized by altered expression of N metabolism genes and differential activity of nitrate reductase (NR) and glutamate dehydrogenase (GDH). It was additionally demonstrated that CV interacts with glutamine synthase 2 (GS2) mediating its degradation. Altogether these results were associated with the activation of N assimilation in RNAiOs CV plants ensuring a superior performance under water stress (Sade et al., 2018).
In the context of darkness-induced carbon starvation , the shift in amino acid metabolism by CV deficiency is likely capable of compromising plant survival, once amino acids are extensively used as energetic substrates under these conditions. Indeed, the impairment of amino acid release in atg mutants leads to energetic failure and differential respiratory response under extended darkness conditions (Barros et al., 2017). Interestingly, the amircv1xatg5 mutants displayed ed lower accumulation of TCA cycle intermediates compared to the atg5 single mutant (Fig. 7). Our previous study associated the higher levels of organic acids to a higher flux through the tricarboxylic acid cycle as a consequence of the respiratory activity in Arabidopsis atg mutants (Barros et al., 2017). The accumulation of TCA cycle intermediates during dark and developmental senescence has previously been suggested as a symptom of higher respiration (Araujo et al., 2010, 2011). In this context, the minor increases of organic acids observed in the amircv1xatg5 mutant suggest that the respiratory activation of the atg5 mutant is somehow restrained in the absence of CV. In addition to chloroplasts, it has been shown that CV is also important in peroxisome and possibly mitochondrial maintenance. In this context, the OsCV rice mutant was characterized by a reduced number of peroxisomes and mitochondria under elevated CO2levels (Umnajkitikorn et al., 2020). Accordingly, the activation of OsCV mediates the removal of the OsPEX11 protein to the vacuole, triggering a reduced number of peroxisomes and decreased catalase activity under elevated CO2 conditions (Umnajkitikorn et al., 2020). The role of CV in peroxisomal protein turnover was also demonstrated in tomato plants submitted to extended darkness wherein SlCV interacts with SlCAT3 leading to excessive accumulation of ROS (Yu et al., 2022). Considering that energy-related pathways occur in different cell compartments, it may be expected that CV participates in the maintenance/degradation of other organelles in addition to chloroplasts. Therefore, the reduced levels of TCA cycle intermediates in the double mutants may also be triggered by a possible differential degradation of peroxisome and mitochondria in the amircv1xatg5 mutants. The accumulation of peroxisome and mitochondrial proteins in atgmutants has been extensively investigated (Shibata et al., 2013; Yoshimoto et al., 2014; Li et al., 2014; Ma et al, 2021; Kacprzak and van Aken, 2022). Despite that, the exact connection between CV and autophagy in maintaining energy-related organelles still needs to be addressed.
To decipher the importance of autophagy and CV pathways in chloroplast maintenance, we paid particular attention to the analysis of chloroplast ultrastructure. It was previously reported that atg5 mutants presented marked changes in chloroplast structure following extended darkness conditions (Barros et al., 2021). Here, we further demonstrated that the disruption of both CV and autophagy leads to a differential chloroplast ultrastructure under extended darkness. Accordingly, theatg5 mutant displayed deformed chloroplasts with a more compromised stromal structure (Fig. 8). Although we observed certain conservation of grana in the chloroplasts of the atg5 mutants, the thylakoid membrane system was static and missed the typical reorganization of darkened chloroplast observed in the WT andamircv-1 lines, characterized by curvature of thylakoid membranes. On the other hand, theamircv1xatg5 chloroplasts partially recovered thylakoid membrane organization, despite showing compromised granal stacking (Fig. 8). It was previously observed that CV overexpression induced chloroplast structural changes, characterized by the unstacking and swelling of the thylakoid membranes which compromised chloroplast stability (Wang and Blumwald, 2014; Yu et al., 2022). Interestingly, our results show that downregulation of CV combined with the absence of autophagy results in more compromised thylakoid and grana structures compared to WT and to the correspondent single mutants under extended darkness. It is worth mentioning that CV was previously proposed to mediate the target of PsbO protein, altering the structure of the photosystem II, and facilitating the access of the thylakoid-associated proteases, such as DEGP1 and FTSH, to chloroplast core proteins (Wang and Blumwald, 2014). The lack of chloroplast repair mediated by proteases results in the accumulation of damaged chloroplast proteins, generating ROS (Kato and Sakamoto et al., 2009), and possibly thereby leading to the deregulation of chloroplast machinery. Therefore, it is tempting to suggest that the selective turnover of envelope proteins by the CV pathway contributes to chloroplast remodeling in the absence of autophagy. It should also be highlighted that lipid composition directly influences the biophysical properties of thylakoid membranes (Mazur et al., 2019). Indeed, recent studies have reported massive changes in galactolipids in plants lacking autophagy (Havé et al., 2019; McLoughlin et al., 2020; Barros et al., 2021). However, the potential roles of CV in chloroplast lipid composition remain to be addressed.
Collectively, the findings described here refine our understanding of chloroplast degradation events during dark-induced senescence. By contrast to the situation observed when autophagy is disrupted, the impairment of CV has a minor impact on plant response to energy deprivation. This highlights the preferential activation of autophagy-mediated pathways to ensure chloroplast maintenance and starvation response under extended darkness. Our data further suggest that CV deficiency triggers minor energetic consequences when autophagy is still present and activated. The further characterization ofamircv1xatg5 double mutants revealed a potential role of CV in the metabolic response and chloroplast remodeling of the atg5mutant during extended darkness. Noteworthy, the early senescence phenotype of the amircv1xatg5 mutants under extended darkness highlights the possible operation of other catabolic pathways. The presence of SAVs in atg5 chloroplast indicates the relevance of this pathway in chloroplast turnover during these conditions. Dissecting the intertwined mechanisms regulating chloroplast turnover are still required to fully understand the exact relation between autophagy, CV and SAVs on chloroplast maintenance and plant stress tolerance.

METHODS

Plant material and dark treatment

Two Arabidopsis RNAi mutant lines for CV gene,amircv-1 and amircv-2 (Wang and Blumwald, 2014), the T-DNA line atg5-1 (SAIL_129B079) and its correspondent WT (Columbia 0 ecotype) were used in this study. Seeds were surface-sterilized and imbibed for 4 days at 4°C in the dark and subsequently germinated. Seedlings grown at 22°C under short-day conditions (8 h light/16 h dark), 60% relative humidity with 150 μmol photons m-2 s-1. amircv mutants were selected by application of Glufosinate-ammonium (120 mg/L) in ten-old day seedlings. For dark treatments, selected seedlings were grown at 22°C under short-day for 4 weeks. Afterwards, plants were maintained in dark in the same growth cabinet. The rosettes were harvested at intervals of 0, 3, 7 and 10 days after transition to darkness and immediately frozen in liquid nitrogen and stored at -80°C until further analysis.