Life and death are essential parts of

the natural cycle of all multicellular

organisms.

THE CELL DEATH

You have made your way from worm to man, and much
within you is still worm.

F. Nietzsche, Thus Spoke Zarathustra, Prologue, Part 3

aciddental, ACD & RCD, regulated
A new species?
Helacyton gartleri?
Dr. Van Valen
The current classification system of cell death has been
updated by the Nomenclature Committee on Cell Death
(NCCD), which formulates guidelines for the definition and
interpretation of all aspects of cell death since 2005.20 The
NCCD has released five position papers dealing with the
classification of cell death (2005 and 2009),20,21 the
molecular definitions of cell death subroutines
(2012),22 essential versus accessory aspects of cell death
(2015),23 and molecular mechanisms of cell death
(2018).24 Currently, cell death can be fundamentally divided
into accidental cell death (ACD) and RCD, based on
functional aspects.23
 Classification of cell death
recommendations of the Nomenclature Committee on Cell Death 2009, Cell Death Differ. 2009 Jan; 16(1): 3–11.
Definition Notes Methods of detection3-5
Molecular or morphological criteria to define dead cells
Loss of plasma membrane integrity Plasma membrane has broken down, resulting (IF) Microscopy and/or FACS to assess the
in the loss of cell’s identity exclusion of vital dyes, in vitro
Cell fragmentation The cell (including its nucleus) has undergone (IF) Microscopy
complete fragmentation into discrete bodies FACS quantification of hypodiploid events
(usually referred to as apoptotic bodies) (sub-G1 peak)
Engulfment by adjacent cells The corpse or its fragments have been (IF) Microscopy
phagocytosed by neighboring cells FACS colocalization studies
Proposed points-of-no return to define dying cells
Massive activation of caspases Caspases execute the classic apoptotic Immunoblotting
program, yet in several instances, caspase- FACS quantification by means of fluorogenic
independent death occurs. Moreover, substrates or specific antibodies
caspases are involved in non-lethal processes
including differentiation and activation of cells
ΔΨm dissipation Protracted ΔΨm loss usually precedes MMP FACS quantification with ΔΨm-sensitive
and cell death; however, transient dissipation probes Calcein-cobalt technique
is not always a lethal event
MMP Complete MMP results in the liberation of IF colocalization studies
lethal catabolic enzymes or activators of such Immunoblotting after subcellular fractionation
enzymes. Nonetheless, partial
permeabilization may not necessarily lead to
cell death
PS exposure PS exposure on the outer leaflet of the plasma FACS quantification of Annexin V binding
membrane often is an early event of
apoptosis, but may be reversible. PS
exposure occurs also in T-cell activation,
without cell death
Operative definition of cell death, in particular in cancer research
Loss of clonogenic survival This method does not distinguish cell death Clonogenic assays
from long-lasting or irreversible cell cycle
arrest
Table 1
Cell death methodology

Abbreviations: ΔΨm, mitochondrial transmembrane permeabilization; FACS, fluorescence-activated cell sorter; IF,
immunofluorescence; MMP, mitochondrial membrane permeabilization; PS, phosphatidylserine
DCD: autophagy-dependent cell death, ICD: immunogenic cell death, LDCD: lysosome-
dependent cell death, MPT: mitochondrial permeability transition.
(calpaínas, catepsinas,
transglutaminases e
nucleases
NECROSE

ONCOSE
 MORTE CELULAR
PATOLOGIA

PATOS = SOFRIMENTO
LOGOS = ESTUDO

RUDOLF LUDWIG KARL

VIRCHOW, 1821-1902
(Patologista Alemão)
OS QUATRO ASPECTOS DAS
DOENÇAS QUE SÃO CENTRAIS NO
ESTUDO DA PATOLOGIA:

1. Sua causa (etiologia);

2. O mecanismo de seu desenvolvimento
(patogênese);
3. As alterações estruturais nas células e
órgãos (alterações morfológicas);
4. As conseqüências funcionais das alterações
morfológicas (significado clínico).
 CAUSAS DE DANO
CELULAR
1. HIPÓXIA
2. AGENTES FÍSICOS
3. AGENTES QUÍMICOS E DROGAS
4. AGENTES INFECCIOSOS
5. REAÇÕES IMUNOLÓGICAS
6. DEFEITOS GENÉTICOS
7. DESEQUILÍBRIOS NUTRICIONAIS
Lesões celulares
reversíveis e
irreversíveis
CÉLULAS RENAIS DO
TÚBULO PROXIMAL.
ULTRAESTRUTURA.
MORTE CELULAR
PROGRAMADA:
APOPTOSE
Figure 18-2 Molecular Biology of the Cell (© Garland Science 2008)
MORTE CELULAR PROGRAMADA: APOPTOSE
A HARMONIA DE UM VERME DEPENDE
DO SUICÍDIO CELULAR: APOPTOSE
 Caenorhabditis elegans

Less than 1000 cells--------15% die

Only 4 genes on control: ced-3 (humans ~10; caspase 9); ced-4 (Apaf1,
apoptotic protease-activating factor 1); ced-9 (humans ~20; bcl2 family-
repressors) and egl-1 (humans; Bax, Bak, Bid, etc.)…………… (protease
dirigida cisteina-aspartato/CASPASE)
 gene supressor de apoptose gene supressor de apoptose

(The Good, which

blocks apoptosis)
gene gene
promotor de The Ugly promotor de
apoptose apoptose
(The Bad, which executes
apoptosis)

Egl1, egg-laying defective

APOPTOSE É UM PROCESSO UNIPRESENTE
EM TODOS OS SERES VIVOS

Robert Horvitz, 1986.

 CASPASES: enzimas com um resíduo
de cisteína capazes de clivar outras
proteínas depois de um resíduo de
ácido aspártico, uma especificidade
incomum entre proteases. O nome
EFFECTORS "caspase" é derivado dessa função
molecular característica: cysteine-
aspartic-acid-proteases.

INICIATORS
 VIA RECEPTOR DE MORTE

Formação do disco de morte

FADD = domínio de morte associado a Fas;

RIP1 = receptor-interacting protein kinase 1
TRADD = TNFR-associated DD
FADD = FAS-associated protein with a DD
cIAPs = cellular inhibitor of apoptosis proteins
TRAIL = TNF-related apoptosis inducing ligand
 VIA MITOCONDRIAL

IAPs = inibidores de apoptose

Apaf = fator ativador de apoptose
Smac/DIABLO (second mithocondria-derived activator
of caspases/Direct IAP-Binding Protein with Low pI)
Apoptossomo
Apaf-1 forms the backbone of the apoptosome. It has
three distinct regions: the N-terminal caspase-
recruitment domain (CARD, residues 1–90), a central
nucleotide-binding and oligomerization region (NB-
ARC/NOD, 128–586) and a C-terminal WD40 region
(613–1248) making up a protein about 140 KDa
 Etapa mais avançada,
em que a membrana
nuclear forma
evaginações contendo
cromatina
condensada. Isto
depois dá origem aos
corpos apoptóticos.

Condensação da cromatina na face interna

da membrana nuclear formando
crescentes em uma célula na fase inicial da
apoptose.

Imagens de microscopia de varredura para mostrar o aspecto de células em

apoptose. À E., célula normal com microvilosidades. À D., célula em
apoptose, mostrando orifícios (crateras) na superfície celular. Estas teriam
ligação com o retículo endoplasmático e levariam à perda de água do interior
da célula para o meio externo.
APOPTOSE –MIC. LUZ
The molecular machinery of regulated cell death
Daolin Tang, Rui Kang, Tom Vanden Berghe, Peter
Vandenabeele & Guido Kroemer
Cell Researchvolume 29, pages347–364 (2019)
 Vascular Endothelial Cell Interactions and Signaling
SIGMA-ALDRICH

Anoikis. Literally meaning ‘the state of being homeless’, this term of ancient
Greek derivation was introduced by Frisch and Francis in 1994 to describe the
apoptotic response of adherent cells due to the absence of cell-to-matrix
interactions.
Entosis. In 2007, Overholtzer et al. introduced the term ‘entosis’ to
describe a cell death mechanism linked to the ‘cell-in-cell’
phenotype that is frequently exhibited by nonphagocytic cells in
clinical tumor samples.
Parthanatos. Coined after Thanatos, the personification of death in Greek
mythology, the term ‘parthanatos’ has been introduced to indicate a particular cell
death mode involving the DNA damage-responsive enzymes poly(ADP-ribose)
polymerases (PARPs), and in particular PARP1, which alone accounts for more
than 90% cellular PARP activity.
Pyroptosis. The term ‘pyroptosis’ has been introduced in 2000 by Brennan and
Cookson to functionally describe the peculiar death of macrophages infected by
Salmonella typhimurium. Several other bacterial triggers of this atypical
cell death modality have been identified, including Shigella flexneri, Listeria
monocytogenes, Pseudomonas aeruginosa, Francisella tularensis and the Bacillus
anthracis toxin. However, it has become clear that pyroptosis neither constitutes a
macrophage-specific process nor a cell death subroutine that only results from
bacterial infection. Of note, pyroptotic cells can exhibit apoptotic and/or necrotic
morphological features.
Netosis. In response to several stimuli, neutrophils and eosinophils can release the
so-called neutrophil extracellular traps (NETs), that is, microbicidal structures
composed of nuclear chromatin, histones and granular antimicrobial proteins.
Netotic cells exhibit massive vacuolization of the cytoplasm, rapid chromatin
decondensation and breakdown of both the nuclear and granular membranes,
which is required for proper NET formation.
 E. coli – programmed death is initiated by
infection by phage. This prevents further
spread of phage to the remaining population.

marsupial mice – Males die 2 weeks after reproducing

from an overabundance of their own pheromones

Saccharomyces cerevisiae –
Under stress the yeast
mitochondria produce ROS,
leading to loss of membrane
potential within the
mitochondria and death of
the cell.
Squid – Some male squid die
immediately after mating.
Evolutionary history
Where we go?
Este é o final do
curso de Biologia
Celular e
Molecular.

Boa sorte em
seus planos
futuros!