Mitochondria are multifunctional subcellular organelles essential for cellular energy homeostasis and apoptotic cell death. It is, therefore, crucial to maintain mitochondrial fitness. Mitophagy, the selective removal of dysfunctional mitochondria by autophagy, is critical for regulating mitochondrial quality control in many physiological processes, including cell development and differentiation. On the other hand, both impaired and excessive mitophagy are involved in the pathogenesis of different ageing-associated diseases such as neurodegeneration, cancer, myocardial injury, liver disease, sarcopenia and diabetes. The best-characterized mitophagy pathway is the PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent pathway. However, other Parkin-independent pathways are also reported to mediate the tethering of mitochondria to the autophagy apparatuses, directly activating mitophagy (mitophagy receptors and other E3 ligases). In addition, the existence of molecular mechanisms other than PINK1-mediated phosphorylation for Parkin activation was proposed. The adenosine5′-monophosphate (AMP)-activated protein kinase (AMPK) is emerging as a key player in mitochondrial metabolism and mitophagy. Beyond its involvement in mitochondrial fission and autophagosomal engulfment, its interplay with the PINK1–Parkin pathway is also reported. Here, we review the recent advances in elucidating the canonical molecular mechanisms and signaling pathways that regulate mitophagy, focusing on the early role and spatial specificity of the AMPK/ULK1 axis.

Objectives: To assess the prevalence and types of genes encoding extended-spectrum β-lactamases (ESBLs) in clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. from Bolivia. Methods: A total of 642 clinical isolates were collected consecutively during a 4 month period (September to December 2004). Resistance or reduced susceptibility to cefotaxime and/or ceftazidime and/or aztreonam was assessed using double disc synergy tests using clavulanic acid, cefotaxime, ceftazidime and aztreonam to identify putative ESBL-producing isolates. The ESBL determinants were characterized by colony blot hybridization, PCR and DNA sequencing. Results: Of the 642 isolates, 220 (34.3%) showed resistance or reduced susceptibility to cefotaxime and/or ceftazidime and/or aztreonam, and 150 (23.4%) were putative ESBL producers. A total of 106 ESBL-producing isolates contained the bla_CTX-M-2 gene, and 32 isolates had a novel allele, bla_CTX-M-43. bla_CTX-M alleles were detected in all P. aeruginosa and Acinetobacter spp. studied. In contrast, only 12 ESBL-producing isolates had bla_PER-2, mainly Enterobacteriaceae, although it was also found in a strain of P. aeruginosa. Conclusions: This is the first study on ESBL-producing strains in Bolivia and it reveals a high prevalence of bla_CTX-M genes. The PER-2 enzyme was less prevalent, but its gene was detected in several species, including P. aeruginosa, which is consistent with horizontal transfer.