MitoStores: chaperone-controlled protein granules store mitochondrial precursors in the cytosol.

Hundreds of nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. However, the early processes associated with mitochondrial protein targeting remain poorly understood. Here, we show that in Saccharomyces cerevisiae, the cytosol has the capacity to transiently store mitochondrial matrix-destined precursors in dedicated deposits that we termed MitoStores. Competitive inhibition of mitochondrial protein import via clogging of import sites greatly enhances the formation of MitoStores, but they also form during physiological cell growth on nonfermentable carbon sources. MitoStores are enriched for a specific subset of nucleus-encoded mitochondrial proteins, in particular those containing N-terminal mitochondrial targeting sequences. Our results suggest that MitoStore formation suppresses the toxic potential of aberrantly accumulating mitochondrial precursor proteins and is controlled by the heat shock proteins Hsp42 and Hsp104. Thus, the cytosolic protein quality control system plays an active role during the early stages of mitochondrial protein targeting through the coordinated and localized sequestration of mitochondrial precursor proteins.

Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol.

The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient samples and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but causalities remain unclear. We used Saccharomyces cerevisiae to analyze how mitochondrial processes regulate the behavior of aggregation-prone polyQ protein derived from human huntingtin. Expression of Q97-GFP rapidly led to insoluble cytosolic aggregates and cell death. Although aggregation impaired mitochondrial respiration only slightly, it considerably interfered with the import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97-GFP, whereas Mia40 overexpression strongly suppressed the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the post-translational import of mitochondrial precursor proteins into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Mia40 regulates this competition as it has a rate-limiting role in mitochondrial protein import. Therefore, Mia40 is a dynamic regulator in mitochondrial biogenesis that can be exploited to stabilize cytosolic proteostasis.

Effects of a Web-Based Behavioral Activation Intervention on Depressive Symptoms, Activation, Motivation, and Volition: Results of a Randomized Controlled Trial.

INTRODUCTION: Behavioral activation (BA) is effective for the treatment of depression. The Health Action Process Approach (HAPA), which is derived from health psychology, can provide a motivational-volitional framework of BA. OBJECTIVE: This study investigated the efficacy of a HAPA-based internet-delivered BA intervention (iBA; called InterAKTIV) in individuals with depression, also assessing HAPA-based motivational and volitional outcomes. METHODS: In a two-arm randomized controlled efficacy trial with a parallel design, 128 participants with a major depressive episode were randomly allocated to the intervention group (IG; TAU + immediate access to iBA) or control group (CG; TAU + access to iBA after follow-up). The primary outcome of clinician-rated depressive symptoms and secondary outcomes were assessed at baseline (T1), 8 weeks (T2), 6-month after randomization (T3). Data were analyzed on an intention-to-treat basis. RESULTS: Linear mixed model analyses revealed a significant group*time interaction effect on clinician-rated depressive symptoms favoring the IG (F2, 156.0 = 7.40; p < 0.001, d = 0.79 at T2, d = 0.25 at T3). The IG was also superior regarding self-rated depressive symptoms, BA, most motivational, and all volitional outcomes. CONCLUSION: This study shows that HAPA-based iBA can significantly improve clinician-rated depressive symptoms, as well as outcomes used in the HAPA model in people with depression. Building on these efficacy results, in the next step, the relationship between BA interventions and activity levels should be investigated, taking into account motivation and volition as potential mediators.

Internet-Based Behavioral Activation for Depression: Systematic Review and Meta-Analysis.

BACKGROUND: Behavioral activation is an effective treatment for reducing depression. As depressive disorders affect many people worldwide, internet-based behavioral activation (iBA) could provide enhanced treatment access. OBJECTIVE: This study aimed to investigate whether iBA is effective in reducing depressive symptoms and to assess the impact on secondary outcomes. METHODS: We systematically searched MEDLINE, PsycINFO, PSYNDEX, and CENTRAL up to December 2021 for eligible randomized controlled trials. In addition, a reference search was conducted. Title and abstract screening, as well as a full-text screening, was conducted by 2 independent reviewers. Randomized controlled trials that investigated the effectiveness of iBA for depression as a treatment or main component were included. Randomized controlled trials had to report depressive symptoms, with a quantitative outcome measure and assess an adult population with depressive symptoms above cutoff. Two independent reviewers performed the data extraction and risk of bias assessment. Data were pooled in random-effects meta-analyses. The primary outcome was self-reported depressive symptoms posttreatment. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. RESULTS: A total of 12 randomized controlled trials, with 3274 participants (88% female, 43.61 years) were included. iBA was more effective in reducing depressive symptom severity posttreatment than inactive control groups (standardized mean difference -0.49; 95% CI -0.63 to -0.34; P<.001). The overall level of heterogeneity was moderate to substantial (I2=53%). No significant effect of iBA on depressive symptoms could be found at 6-month follow-up. Participants assigned to iBA also experienced a significant reduction of anxiety and a significant increase in quality of life and activation compared to the inactive control groups. The results remained robust in multiple sensitivity analyses. The risk of bias assessment revealed at least some concerns for all studies, and there was evidence of slight publication bias. CONCLUSIONS: This systematic review and meta-analysis implies that iBA is effective in reducing depressive symptoms. It represents a promising treatment option, providing treatment access where no treatment is available yet. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews CRD42021236822; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=236822.

The intermembrane space protein Mix23 is a novel stress-induced mitochondrial import factor.

The biogenesis of mitochondria requires the import of hundreds of precursor proteins. These proteins are transported post-translationally with the help of chaperones, meaning that the overproduction of mitochondrial proteins or the limited availability of chaperones can lead to the accumulation of cytosolic precursor proteins. This imposes a severe challenge to cytosolic proteostasis and triggers a specific transcription program called the mitoprotein-induced stress response, which activates the proteasome system. This coincides with the repression of mitochondrial proteins, including many proteins of the intermembrane space. In contrast, herein we report that the so-far-uncharacterized intermembrane space protein Mix23 is considerably up-regulated when mitochondrial import is perturbed. Mix23 is evolutionarily conserved and a homolog of the human protein CCDC58. We found that, like the subunits of the proteasome, Mix23 is under control of the transcription factor Rpn4. It is imported into mitochondria by the mitochondrial disulfide relay. Mix23 is critical for the efficient import of proteins into the mitochondrial matrix, particularly if the function of the translocase of the inner membrane 23 is compromised such as in temperature-sensitive mutants of Tim17. Our observations identify Mix23 as a novel regulator or stabilizer of the mitochondrial protein import machinery that is specifically up-regulated upon mitoprotein-induced stress conditions.

Effectiveness of a Guided Web-Based Intervention to Reduce Depressive Symptoms before Outpatient Psychotherapy: A Pragmatic Randomized Controlled Trial.

INTRODUCTION: Psychotherapy is a first-line treatment for depression. However, capacities are limited, leading to long waiting times for outpatient psychotherapy in health care systems. Web-based interventions (WBI) could help to bridge this treatment gap. OBJECTIVE: This study investigates the effectiveness of a guided cognitive-behavioral WBI in depressive patients seeking face-to-face psychotherapy. METHODS: A 2-arm randomized controlled trial was conducted. Depressive patients (n = 136) recruited from the waiting lists of outpatient clinics were randomly assigned to an intervention group (IG; treatment as usual [TAU] + immediate access to WBI) or a control group (CG; TAU + access to WBI after follow-up). Depressive symptoms and secondary outcomes were assessed at baseline, 7 weeks, and 5 months after randomization. RESULTS: Mixed-model analyses revealed a significant group × time interaction effect on depressive symptoms (F2, 121.5 = 3.91; p < 0.05). Between-group effect sizes were d = 0.55 at 7 weeks and d = 0.52 at 5 months. The IG was superior regarding psychological symptoms and mental health quality of life but not on physical health quality of life, attitudes, motivation for psychotherapy, or subjective need and uptake of psychotherapy. CONCLUSIONS: Patients waiting for face-to-face psychotherapy can benefit from a WBI when compared to TAU. Despite the reduction of depressive symptoms in the IG, the uptake of subsequent psychotherapy was still high in both groups. The effects remained stable at the 5-month follow-up. However, this study could not determine the proportion of specific intervention effects vs. nonspecific effects, such as positive outcome expectations or attention. Future research should focus on the long-term effects and cost-effectiveness of WBI before psychotherapy.

[Implementation of a Web-Based Self-Help Intervention for Mood Enhancement during Waiting Times for Outpatient Psychotherapy - A Qualitative Study Exploring Participants' Perspectives]. / Webbasierte Selbsthilfe zur Stimmungsverbesserung in der Wartezeit auf ambulante Psychotherapie ­ Eine qualitative Erhebung der Teilnehmerperspektive.

OBJECTIVE: In Germany, waiting times for outpatient psychotherapy are on average 5 months long. Guided web-based interventions can be implemented to reduce depressive symptoms during waiting times. The study aims to explore how patients experience the usage of a web-based intervention for mood enhancement. METHODS: Patients on the waiting lists of cooperating outpatient clinics were invited to participate in the study and apply a web-based intervention for mood enhancement. Eleven participating patients were interviewed about their experiences with the intervention. The data was analyzed based on the Grounded-Theory methodology. RESULTS: Three categories could be derived from the data: prior expectations, experiences with the intervention and factors influencing adherence. The web-based intervention was experienced very differently and was associated with both positive and negative experiences. The participants could be grouped into 3 user types. DISCUSSION: Not all patients report positive experiences with the intervention and some fail to adhere. In order to prepare patients adequately, they should be informed about the application and goals of the intervention in advance. Interventions should be implemented in accordance with the individual's need of support in order to enhance adherence and allow positive experiences.

Local, collaborative, stepped and personalised care management for older people with chronic diseases (LoChro): study protocol of a randomised comparative effectiveness trial.

BACKGROUND: Multimorbid older adults suffering from a long-term health condition like depression, diabetes mellitus type 2, dementia or frailty are at high risk of losing their autonomy. Disability and multimorbidity in the older population are associated with social inequality and lead to soaring costs. Our local, collaborative, stepped and personalised care management for older people with chronic diseases (LoChro-Care) aims at improving outcomes for older multimorbid patients with chronic conditions whose social and medical care must be improved. METHODS: The study will evaluate the effects of LoChro-Care on functional health, depressive symptoms and satisfaction with care, resource utilisation as well as health costs in older persons with long-term conditions. The trial will compare the effectiveness of LoChro-Care and usual care in a cross-sectoral setting from hospital to community care. We will recruit 606 older adults (65+) admitted to local hospital inpatient or outpatient departments who are at risk of loss of independence. Half of them will be randomised to receive the LoChro-Care intervention, comprising seven to 16 contacts with chronic care managers (CCM) within 12 months. The hypothesis that LoChro-Care will result in better patient-centred outcomes will be tested through mixed-method process and outcome evaluation and valid measures completed at baseline and at 12 and 18 months. Cost-effectiveness analyses from the healthcare perspective will include incremental cost-effectiveness ratios. DISCUSSION: The trial will provide evidence about the effectiveness of local, collaborative, stepped and personalised care management for multimorbid patients with more than one functional impairment or chronic condition. Positive results will be a first step towards the implementation of a systematic cross-sectoral chronic care management to facilitate the appropriate use of available medical and nursing services and to enhance self-management of older people. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00013904 ; Trial registration date: 02. February 2018.

Correction: A Web-Based Acceptance-Facilitating Intervention for Identifying Patients' Acceptance, Uptake, and Adherence of Internet- and Mobile-Based Pain Interventions: Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/jmir.9925.].

[Low-Intensity Interventions to Reduce Depressive Symptoms before Outpatient Psychotherapy - A Systematic Literature Review]. / Niedrigintensive Interventionen zur Reduktion depressiver Symptome vor Beginn einer ambulanten Psychotherapie.

Psychotherapeutic resources are limited, leading to prolonged waiting periods prior to outpatient psychotherapy. Low-intensity interventions have the potential to bridge such treatment gaps. This systematic review aims to identify interventions targeting depressive symptoms implemented prior to outpatient psychotherapy, and to assess their effectiveness and acceptance. 22 studies were identified. Interventions were classified as active waiting, self-help, guided self-help, brief single-strand interventions, and low-intensity psychotherapy. Evidence of intervention effectiveness is limited; intervention acceptance varies between interventions. The resulting classification illustrates a range of innovative interventions which can be implemented into routine care depending on existing resources and preferences. Different models for the provision of low-intensity interventions are discussed.

[New Media in Psychotherapy: Blended Therapy from the Perspective of Outpatient Psychotherapists]. / Neue Medien in der Psychotherapie: Blended Therapy aus der Sicht ambulanter Psychotherapeuten.

The aim of the study was to generate a model describing psychotherapists' use of new media in outpatient psychotherapy. Problem-centered interviews were conducted with 12 outpatient psychotherapists. Data was analyzed following the Grounded Theory approach. The interviews revealed five categories that were integrated into the model "Use of new media in outpatient therapy" (MAP): First, psychotherapists' characteristics determine whether new media use is considered. When new media is in use, patient characteristics define its intensity and content. Additionally, decision making rules and communication rules shape therapists' use of new media. MAP identifies barriers and facilitators of new media application in outpatient psychotherapy and describes psychotherapists' decision making process. Options for implementing blended therapy in outpatient psychotherapeutic care are discussed.

[Responses of German-speaking voice assistants to questions about health issues]. / Antwortverhalten von deutschsprachigen Sprachassistenten auf Gesundheitsfragen.

BACKGROUND: In Germany, there is widespread use of smartphones that can be operated via voice assistants (VAs). Due to their increasing distribution, they hold the potential to influence health behavior at a population level. OBJECTIVES: This study examines the response behavior of German-speaking VAs to questions on mental and physical health as well as interpersonal violence. METHODS: Common VAs received nine standardized health questions. Responses were evaluated in terms of the categories "Recognizing the question," "Respectful responsiveness," and "Referring to support services." RESULTS: Fifty-one VAs were tested on 44 devices. Mental health issues were mostly recognized and answered with respect. Regarding expressed suicidal thoughts, only one VA did not refer to a specific crisis line. With respect to "interpersonal violence," only one VA recognized the expressed problems. In terms of physical health, only one VA showed respectful responses in all three tested healthcare areas, leading help seekers to additional healthcare services (e.g., hospitals, pharmacies). For some complaints, the VAs gave behavioral advice. CONCLUSION: VAs are able to recognize health issues, to respond respectably, and to guide those in need of care to specific healthcare and counselling services. However, responsiveness is insufficient and inconsistent. Future research should investigate how the responsiveness of VAs can be improved to provide the best possible support to people in crisis.

The effect of a new lifetime-cardiovascular-risk display on patients' motivation to participate in shared decision-making.

BACKGROUND: This study investigated the effects of three different risk displays used in a cardiovascular risk calculator on patients' motivation for shared decision-making (SDM). We compared a newly developed time-to-event (TTE) display with two established absolute risk displays (i.e. emoticons and bar charts). The accessibility, that is, how understandable, helpful, and trustworthy patients found each display, was also investigated. METHODS: We analysed a sample of 353 patients recruited in general practices. After giving consent, patients were introduced to one of three fictional vignettes with low, medium or high cardiovascular risk. All three risk displays were shown in a randomized order. Patients were asked to rate each display with regard to motivation for SDM and accessibility. Two-factorial repeated measures analyses of variance were conducted to compare the displays and investigate possible interactions with age. RESULTS: Regarding motivation for SDM, the TTE elicited the highest motivation, followed by the emoticons and bar chart (p < .001). The displays had no differential influence on the age groups (p = .445). While the TTE was generally rated more accessible than the emoticons and bar chart (p < .001), the emoticons were only superior to the bar chart in the younger subsample. However, this was only to a small effect (interaction between display and age, p < .01, η 2 = 0.018). CONCLUSIONS: Using fictional case vignettes, the novel TTE display was superior regarding motivation for SDM and accessibility when compared to established displays using emoticons and a bar chart. If future research can replicate these results in real-life consultations, the TTE display will be a valuable addition to current risk calculators and decision aids by improving patients' participation.

A Web-Based Acceptance-Facilitating Intervention for Identifying Patients' Acceptance, Uptake, and Adherence of Internet- and Mobile-Based Pain Interventions: Randomized Controlled Trial.

BACKGROUND: Internet- and mobile-based interventions are effective for the treatment of chronic pain. However, little is known about patients' willingness to engage with these types of interventions and how the uptake of such interventions can be improved. OBJECTIVE: The aim of this study was to identify people's acceptance, uptake, and adherence (primary outcomes) with regard to an internet- and mobile-based intervention for chronic pain and the influence of an information video as an acceptance-facilitating intervention (AFI). METHODS: In this randomized controlled trial with a parallel design, we invited 489 individuals with chronic pain to participate in a Web-based survey assessing the acceptance of internet- and mobile-based interventions with the offer to receive an unguided internet- and mobile-based intervention for chronic pain after completion. Two versions of the Web-based survey (with and without AFI) were randomly sent to two groups: one with AFI (n=245) and one without AFI (n=244). Participants who completed the Web-based survey with or without AFI entered the intervention group or the control group, respectively. In the survey, the individuals' acceptance of pain interventions, measured with a 4-item scale (sum score ranging from 4 to 20), predictors of acceptance, sociodemographic and pain-related variables, and physical and emotional functioning were assessed. Uptake rates (log in to the intervention) and adherence (number of completed modules) to the intervention was assessed 4 months after intervention access. To examine which factors influence acceptance, uptake rate, and adherence in the internet- and mobile-based interventions, we conducted additional exploratory subgroup analyses. RESULTS: In total, 57 (intervention group) and 58 (control group) participants in each group completed the survey and were included in the analyses. The groups did not differ with regard to acceptance, uptake rate, or adherence (P=.64, P=.56, P=.75, respectively). Most participants reported moderate (68/115, 59.1%) to high (36/115, 31.3%) acceptance, with 9.6% (11/115) showing low acceptance (intervention group: mean 13.91, SD 3.47; control group: mean 13.61, SD 3.50). Further, 67% (38/57, intervention group) and 62% (36/58, control group) had logged into the intervention. In both groups, an average of 1.04 (SD 1.51) and 1.14 (SD 1.90) modules were completed, respectively. CONCLUSIONS: The informational video was not effective with regard to acceptance, uptake rate, or adherence. Despite the high acceptance, the uptake rate was only moderate and adherence was remarkably low. This study shows that acceptance can be much higher in a sample participating in an internet- and mobile-based intervention efficacy trial than in the target population in routine health care settings. Thus, future research should focus not only on acceptance and uptake facilitating interventions but also on ways to influence adherence. Further research should be conducted within routine health care settings with more representative samples of the target population. TRIAL REGISTRATION: German Clinical Trial Registration DRKS00006183; http://www.drks.de/drks_web/navigate.do ?navigationId=trial.HTML&TRIAL_ID=DRKS00006183 (Archived by WebCite at http://www.webcitation.org/70ebHDhne).

Wound morphology in contact shots from blank cartridge handguns: a study on composite models.

It is a well-known fact that blank cartridge guns can cause penetrating and even fatal injuries when discharged in contact or at very close ranges. In these cases, the gas jet perforates the skin leaving an entrance wound similar to that from a conventional gun. In order to investigate the wound morphology in contact shots from blank firearms, test shots were fired at composite models of pig skin and gelatin blocks using three different calibre 9-mm blank cartridge handguns (two pistols and one revolver) and two types of ammunition. It turned out that the penetrating gas jet produced roundish skin defects resembling bullet entrance holes. Small skin particles from the perforation site were dispersed in the underlying simulant where radiating cracks containing greyish gunshot residues indicated the original expansion of the inrushing combustion gases. Apart from the size of the permanent entrance hole in the skin and the final position of the displaced tissue particles, the penetration depth of the gas jet was determined. Under the specified conditions of the test shots, the zone of mechanical destruction within the simulant was 2.2 to 6.1 cm in length, which illustrates the injuring potential of contact shots inflicted with blank cartridge handguns.

A patterned abrasion caused by the impact of a cartridge case may simulate an atypical muzzle imprint mark.

In contact shots, the muzzle imprint is an informative finding associated with the entrance wound. It typically mirrors the constructional components being in line with the muzzle or just behind. Under special conditions, other patterned skin marks located near a gunshot entrance wound may give the impression to be part of the muzzle imprint. A potential mechanism causing a patterned pressure abrasion in close proximity to the bullet entrance site is demonstrated on the basis of a suicidal shot to the temple. The skin lesion in question appeared as a ring-shaped excoriation with a diameter corresponding to that of the cartridge case. Two hypotheses concerning the causative mechanism were investigated by test shots: - After being ejected, the cartridge case ricocheted inside a confined space (car cabin in the particular case) and secondarily hit the skin near the gunshot entrance wound. - The ejection of the cartridge case failed so that the case became stuck in the ejection port and its mouth contacted the skin when the body collapsed after being hit.

[Death by avalanche in the minor mountain range]. / Lawinentod im Mittelgebirge.

On 30 Jan 2015, two avalanche accidents happened in the Black Forest (at the foot of the 1493 m high Feldberg and the Herzogenhorn situated next to it), in which experienced ski tourers--a 58-year-old woman and a 20-year-old man--were completely buried by snow masses. Both victims were recovered dead after nearly 2 hours under the snow. The avalanches were promoted by strong snowfalls, snowdrift by the wind and steep downwind slopes. One of the victims, the 20-year-old man, underwent a forensic autopsy. The findings suggested death by protracted asphyxiation with agonal hypothermia. A mechanical traumatization with internal injuries suspected by the emergency doctor at the scene could not be confirmed at autopsy. The possible causes of death in the avalanche are discussed using the reported case as an example and in reference to the relevant literature.

[Fire disaster due to deflagration of a propane gas-air mixture]. / Folgenschwerer Brand durch Entzündung eines Propangas-Luft-Gemisches.

On 26 Nov 2012, a serious fire occurred at Neustadt/Black Forest in which 14 persons in a sheltered workshop died and 10 other individuals were injured. The fire was caused by the unbridled escape of propane gas due to accidental disconnection of the screw fixing between a gas bottle and a catalytic heater. Deflagration of the propane gas-air mixture set the workshop facilities on fire. In spite of partly extensive burns the fatally injured victims could be rapidly identified. The results of the fire investigations at the scene and the autopsy findings are presented. Carboxyhemoglobin concentrations ranged between 8 and 56 % and signs of fire fume inhalation were present in all cases. Three victims had eardrum ruptures due to the sudden increase in air pressure during the deflagration.

Curated mode-of-action data and effect concentrations for chemicals relevant for the aquatic environment.

Chemicals in the aquatic environment can be harmful to organisms and ecosystems. Knowledge on effect concentrations as well as on mechanisms and modes of interaction with biological molecules and signaling pathways is necessary to perform chemical risk assessment and identify toxic compounds. To this end, we developed criteria and a pipeline for harvesting and summarizing effect concentrations from the US ECOTOX database for the three aquatic species groups algae, crustaceans, and fish and researched the modes of action of more than 3,300 environmentally relevant chemicals in literature and databases. We provide a curated dataset ready to be used for risk assessment based on monitoring data and the first comprehensive collection and categorization of modes of action of environmental chemicals. Authorities, regulators, and scientists can use this data for the grouping of chemicals, the establishment of meaningful assessment groups, and the development of in vitro and in silico approaches for chemical testing and assessment.

The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering nonimported proteins.

Almost all mitochondrial proteins are synthesized in the cytosol and subsequently targeted to mitochondria. The accumulation of nonimported precursor proteins occurring upon mitochondrial dysfunction can challenge cellular protein homeostasis. Here we show that blocking protein translocation into mitochondria results in the accumulation of mitochondrial membrane proteins at the endoplasmic reticulum, thereby triggering the unfolded protein response (UPRER). Moreover, we find that mitochondrial membrane proteins are also routed to the ER under physiological conditions. The level of ER-resident mitochondrial precursors is enhanced by import defects as well as metabolic stimuli that increase the expression of mitochondrial proteins. Under such conditions, the UPRER is crucial to maintain protein homeostasis and cellular fitness. We propose the ER serves as a physiological buffer zone for those mitochondrial precursors that cannot be immediately imported into mitochondria while engaging the UPRER to adjust the ER proteostasis capacity to the extent of precursor accumulation.