Proteome plasticity in response to persistent environmental change.

Temperature is a variable component of the environment, and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses, resulting in refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to reduction of temperature-sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find that many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and, importantly, cellular functions. We postulate that, in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.

Nascent mitochondrial proteins initiate the localized condensation of cytosolic protein aggregates on the mitochondrial surface.

Eukaryotes organize cellular contents into membrane-bound organelles and membrane-less condensates, for example, protein aggregates. An unsolved question is why the ubiquitously distributed proteins throughout the cytosol give rise to spatially localized protein aggregates on the organellar surface, like mitochondria. We report that the mitochondrial import receptor Tom70 is involved in the localized condensation of protein aggregates in budding yeast and human cells. This is because misfolded cytosolic proteins do not autonomously aggregate in vivo; instead, they are recruited to the condensation sites initiated by Tom70's substrates (nascent mitochondrial proteins) on the organellar membrane using multivalent hydrophobic interactions. Knocking out Tom70 partially impairs, while overexpressing Tom70 increases the formation and association between cytosolic protein aggregates and mitochondria. In addition, ectopic targeting Tom70 and its substrates to the vacuole surface is able to redirect the localized aggregation from mitochondria to the vacuolar surface. Although other redundant mechanisms may exist, this nascent mitochondrial proteins-based initiation of protein aggregation likely explains the localized condensation of otherwise ubiquitously distributed molecules on the mitochondria. Disrupting the mitochondrial association of aggregates impairs their asymmetric retention during mitosis and reduces the mitochondrial import of misfolded proteins, suggesting a proteostasis role of the organelle-condensate interactions.

Implementing the NCTSN Trauma-Informed Organizational Assessment (TIOA) for Improving Trauma-Informed Care in Inpatient Child Psychiatry.

BACKGROUND: Children and adolescents receiving inpatient psychiatric services have disproportionately high levels of exposure to trauma and adversity. The National Child Traumatic Stress Network Trauma-Informed Organizational Assessment (TIOA) is a comprehensive tool intended to guide implementation of trauma-informed care, but it has not yet been applied in inpatient settings. AIMS: The purpose of this quality improvement project was to describe trauma-informed care in inpatient child/adolescent psychiatry with the TIOA, examine relatedness among trauma-informed care domains, and explore barriers or facilitators to applying trauma-informed care. METHODS: This quality improvement project used mixed methods. We conducted a web-based survey in Summer 2022 with staff members (clinical and administrative) at two inpatient child/adolescent psychiatric units in California to assess trauma-informed care practices with the TIOA (87 items). Qualitative follow-up interviews were offered to interested participants. A correlation matrix and cluster analyses were used to examine relationships among TIOA domains; qualitative data were analyzed thematically. RESULTS: There were 69 survey respondents and seven qualitative interviews. TIOA domain scores ranged from a low of 2.3 to a high of 3.2, indicating that practices were occurring only "rarely" to "sometimes." There were two major themes identified from qualitive interviews: (a) barriers to trauma-informed care in an inpatient context that can be resource-constrained or coercive; and (b) discovering strategies to provide trauma-informed care despite structural barriers. CONCLUSION: Organizational interventions targeting any domains of trauma-informed care are needed in inpatient settings given limited uptake of trauma-informed care.

Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.

Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here, we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.