Non‐canonical roles for caveolin in regulation of membrane repair and mitochondria: implications for stress adaptation with age

Abstract

Many different theories of ageing have been proposed but none has served the unifying purpose of defining a molecular target that can limit the structural and functional decline associated with age that ultimately leads to the demise of the organism. We propose that the search for a molecule with these unique properties must account for regulation of the signalling efficiency of multiple cellular functions that degrade with age due to a loss of a particular protein. We suggest caveolin as one such molecule that serves as a regulator of key processes in signal transduction. We define a particular distinction between cellular senescence and ageing and propose that caveolin plays a distinct role in each of these processes. Caveolin is traditionally thought of as a membrane‐localized protein regulating signal transduction via membrane enrichment of specific signalling molecules. Ultimately we focus on two non‐canonical roles for caveolin – membrane repair and regulation of mitochondrial function – which may be novel features of stress adaptation, especially in the setting of ageing. The end result of preserving membrane structure and mitochondrial function is maintenance of homeostatic signalling, preserving barrier function, and regulating energy production for cell survival and resilient ageing.

Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection

“…Caveolae have at least four major functions: (i) as signaling platforms in the membrane, for example for receptor tyrosine kinases (RTKs) including the InsR [ 131 ], GPCRs [ 165 ], eNOS [ 255 ], other signaling proteins [ 256 ] and ion channels [ 166 ]; (ii) regulating fatty acid transport [ 257 , 258 ] and glucose handling [ 158 ]; (iii) participating in mechanotransduction and acting as membrane ‘reservoirs’ to limit damage with mechanical stress [ 167 , 259 ]; and (iv) functioning as membrane transport vesicles, budding from the membrane in response to specific cues and participating in membrane repair [ 260 ]. Abnormalities within these regulatory domains will thus influence ion and substrate movement, protective signaling and myocyte responses to mechanical perturbation, impairing cardiac responses to both pathologic insult and potential therapies.…”

Sarcolemmal dependence of cardiac protection and stress‐resistance: roles in aged or diseased hearts

“…For example, the expression profile for caveolins from neonate, young and aged tissue varies significantly between heart and lung (Kawabe et al ., ). Indeed, as noted in a recent review (Schilling and Patel, ), there appear key differences in age‐associated caveolae/caveolin expression between proliferative and terminally differentiated cell types. Assuming links between caveolae, cholesterol and fluidity, then one must consider organ‐ and cell‐specific responses when interpreting data on the effects of age and disease.…”

A Deeper Look into the Cellular Caves: Caveolins, Cavins and Popdc Proteins in Cardioprotection

“…Caveolae are gaining increasing recognition in relation to cardiac aging as the expression of Cav-3 protein and formation of morphological caveolae have been shown to be reduced in aged mice myocardium (74-week old) as well as in the failing human heart. 82,86,87 Similarly, age-related reductions in caveolins and caveolae expression are also reported in bladder smooth muscle, 88 neurons 89 and muscle cells. 90 Due to the limited availability of clinical atrial/ventricular tissue, a detailed expression analysis of caveolae and its coat proteins has not been conducted in human specimens although the reduction of efficacy of GPCR-mediated cardioprotection has been documented in 75±2 year old human atrial preperations.…”

“…7 It should be noted that caveolae, in addition to enhancing signaling, are also capable of inhibiting signaling. The putative caveolin scaffolding domain (82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101) has been shown to inhibit many ligands that are cardioprotective including eNOS and matrix metalloproteinase-2 in the heart. 14,15 All of these findings suggest that caveolae in conjunction with caveolin proteins concentrate GPCRs and their subunits to allow efficient signal transduction.…”