Edited by John M. DenuDiverse protein import pathways into mitochondria use translocons on the outer membrane (TOM) and inner membrane (TIM). We adapted a genetic screen, based on Ura3 mistargeting from mitochondria to the cytosol, to identify small molecules that attenuated protein import. Small molecule mitochondrial import blockers of the Carla Koehler laboratory (MB)-10 inhibited import of substrates that require the TIM23 translocon. Mutational analysis coupled with molecular docking and molecular dynamics modeling revealed that MB-10 binds to a specific pocket in the C-terminal domain of Tim44 of the protein-associated motor (PAM) complex. This region was proposed to anchor Tim44 to the membrane, but biochemical studies with MB-10 show that this region is required for binding to the translocating precursor and binding to mtHsp70 in low ATP conditions. This study also supports a direct role for the PAM complex in the import of substrates that are laterally sorted to the inner membrane, as well as the mitochondrial matrix. Thus, MB-10 is the first small molecule modulator to attenuate PAM complex activity, likely through binding to the C-terminal region of Tim44.

Tim17 and Tim23 are the main subunits of the TIM23 complex, one of the two major essential mitochondrial inner-membrane protein translocon machineries (TIMs). No chemical probes that specifically inhibit TIM23-dependent protein import were known to exist. Here we show that the natural product stendomycin, produced by Streptomyces hygroscopicus, is a potent and specific inhibitor of the TIM23 complex in yeast and mammalian cells. Furthermore, stendomycin-mediated blockage of the TIM23 complex does not alter normal processing of the major regulatory mitophagy kinase PINK1, but TIM23 is required to stabilize PINK1 on the outside of mitochondria to initiate mitophagy upon membrane depolarization.

Plantar fasciitis is one of the most common complaints of chronic rearfoot heel pain seen by primary care providers. The etiology and differential diagnosis are numerous, as are treatment options. This article includes a definition of plantar fasciitis, anatomy, predisposing factors, physical examination techniques, differential diagnosis, and conservative nonsurgical treatment options. Plantar fasciitis may be acute, but is more often a chronic condition that is directly related to physical activity. The most common complaint is intense heel pain with the first step from bed in the morning and initial step after resting. This pain subsides with time, but returns in the evening after prolonged standing.

Neurodegenerative diseases have been linked to a dysfunctional mitochondrial quality control system that is partially maintained by proteins PINK1 and Parkin. Whereas mitophagy pathways are becoming well-characterized, less is known about the molecular mechanisms of PINK1 trafficking in mitochondria. Accordingly, we have used a small molecule probe (MitoBloCK-10/MB-10) that modulates the activity of TIMM44, an essential component of the protein associated motor (PAM) complex for the mitochondrial inner membrane (TIM23) translocase, to characterize PINK1 import. MB-10 did not inhibit the import or degradation of PINK1 in energized mitochondria. However, when mitophagy was induced by the addition of an uncoupler or respiratory inhibitor, MB-10 treatment altered PINK1 trafficking by inhibiting association with the TOM complex and impairing Parkin recruitment and subsequent mitophagy. MB-10 analogs that did not inhibit TIMM44 activity failed to impair mitophagy, thereby assigning specificity to MB-10. Because PINK1 undergoes lateral release from the TIM23 translocon to interact with inner membrane (IM) modulators, our studies support that TIMM44 may be a key regulator and that the PAM complex has a central role in regulating PINK1-dependent mitophagy. Our studies also provide a probe for dissecting PINK1/Parkin events for mitochondria as well as studying PINK1-dependent mitophagy in cell and animal models.

PurposeThe purpose is to report on the mental health response to the Grenfell incident within the London Fire Brigade (LFB).Design/methodology/approachThe LFB implemented screening for the symptoms of posttraumatic stress disorder (PTSD) at 28 days, 3 months and 6 months for all personnel directly involved in the incident.FindingsThe prevalence of PTSD within frontline personnel was 13.4% at 28 days, falling to 7.6% at 6 months. The LFB's internal Counselling and Wellbeing Service offered treatment to those scoring above the cut-off for PTSD along with accepting self-referral and referrals from line managers and occupational health. There were 139 referrals within the 12-month period following the incident.Research limitations/implicationsThe outcomes for those who engaged in treatment are broadly in line with other studies evaluating post-disaster interventions. Issues for consideration within national guidelines are discussed.Practical implicationsThe screen and treat approach adopted by LFB was shown to be a feasible approach to use within such a scenario.Originality/valueThe current study reports on a screen and treat approach to one of the largest single incidents in the UK in recent years.