Brunk U T, Jones C B, Sohal R S
Department of Pathology, University of Linköping, Sweden.
Mutat Res. 1992 Sep;275(3-6):395-403. doi: 10.1016/0921-8734(92)90042-n.
Based on a series of experiments, using cultured postmitotic neonatal rat cardiac myocytes as a model system, we present a novel hypothesis of lipofuscin formation. This hypothesis proposes that lipofuscin is formed within secondary lysosomes due to an interplay of two processes, the production of partially reduced oxygen species by mitochondria and the autophagocytotic degradation within secondary lysosomes. Specifically, it is proposed that H2O2 generated by mitochondria and other organelles permeates into the lumen of secondary lysosomes, which contain iron derived from cellular structures undergoing intralysosomal degradation. The interaction between reactive ferrous iron and H2O2 results, via Fenton-type mechanisms, in the generation of hydroxyl free radicals (OH), inducing lipid peroxidation and eventually leading to intermolecular cross-linking and lipofuscin formation. Additionally, mitochondria undergoing intralysosomal decomposition might continue for a certain period to produce superoxide anion radicals (O2-) and thus also H2O2. This model of lipofuscinogenesis could satisfactorily explain the variations observed in the rates of lipofuscinogenesis among different postmitotic cell types in various species. Such variations might arise from a variety of factors including differences in the efficiency of the 'anti-oxidative shield', rate of H2O2 generation, amount of chain-breaking antioxidants, mode of intralysosomal iron chelation, rate of autophagocytosis as well as degree of efficiency of the intralysosomal hydrolytic enzymes.
基于一系列实验，我们以培养的新生大鼠有丝分裂后心肌细胞作为模型系统，提出了一种关于脂褐素形成的新假说。该假说认为，脂褐素是在次级溶酶体内形成的，这是由于两个过程相互作用的结果，即线粒体产生部分还原的氧物种以及次级溶酶体内的自噬降解。具体而言，该假说提出线粒体和其他细胞器产生的过氧化氢渗透到次级溶酶体腔内，次级溶酶体含有来自经历溶酶体内降解的细胞结构的铁。通过芬顿型机制，活性亚铁离子与过氧化氢之间的相互作用导致羟基自由基（OH）的产生，诱导脂质过氧化，最终导致分子间交联和脂褐素形成。此外，经历溶酶体内分解的线粒体可能会在一定时期内继续产生超氧阴离子自由基（O2-），进而也产生过氧化氢。这种脂褐素生成模型可以令人满意地解释在不同物种的不同有丝分裂后细胞类型中观察到的脂褐素生成速率的变化。这些变化可能源于多种因素，包括“抗氧化屏蔽”效率、过氧化氢生成速率、链断裂抗氧化剂的量、溶酶体内铁螯合模式、自噬速率以及溶酶体水解酶的效率程度等方面的差异。
